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1
Schrader, Kasmintan Alexandra. "Characterization of hereditary cancer syndromes." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44512.
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Hereditary cancer syndromes predispose to early-onset or multiple cancers in a person or family, follow Mendelian inheritance patterns and demonstrate stereotyped patterns of tumor development. Genotype-phenotype correlations direct clinical genetic testing and provide guidance for hereditary cancer management. This thesis began by examining the association of lobular breast cancer with germline mutations in CDH1, the gene encoding the epithelial cell-cell adhesion molecule E-cadherin and tested whether CDH1 represented a high-frequency breast cancer susceptibility gene, apart from its association with hereditary diffuse gastric cancer. In addition it examined other genotype-phenotype correlations including the association between granular cell tumors and a multiple congenital anomaly syndrome, the specific correlation between a recurrent somatic mutation in a transcription factor and adult-type granulosa cell tumors and the strong association of germline BRCA1 and BRCA2 mutations with high-grade serous epithelial ovarian cancer. These candidate gene analyses were performed using low-throughput molecular technologies. With the advent of cheaper DNA-sequencing capabilities, the application of these new technologies to novel Mendelian disease gene discovery and hereditary cancer management became the subsequent focus of the thesis. Objectives: To determine the frequency of germline CDH1 mutations in women with lobular breast cancer unselected for familial gastric cancer; to define the associations between several alternative genotype-phenotype correlations; and, to apply next-generation sequencing to determine the basis of a Mendelian disorder, in order to determine its utility as a potential familial cancer gene discovery and clinical tool. Selected Methods: Single amplicon mutation screening and sequence analysis of a large cohort of women with early-onset or familial lobular breast cancer. Next-generation sequencing analysis of a family with multiple individuals cosegregating spondyloepiphyseal dysplasia and retinitis pigmentosa. Results: Without a selective history of diffuse gastric cancer, potentially pathogenic germline mutations in CDH1 occured in women with early-onset or hereditary lobular breast cancer in less than two percent of individuals. Diagnosis of a Mucolipidosis type III gamma was possible using new sequencing technologies. Conclusion: There is utility in understanding genotype-phenotype correlations in order to direct genetic testing and novel gene identification. Next-generation sequencing technologies can succesfully be applied to Mendelian disorders with clear phenotypes for gene discovery.
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Moisio, Anu-Liisa. "Predisposing and modifying genes in hereditary colorectal cancer syndromes." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/moisio/.
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Awad, Fawaz. "Pathophysiology of hereditary recurrent fever syndromes : cellular and molecular approaches." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066394.
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Les fièvres récurrentes héréditaires (FRH) sont des maladies auto-inflammatoires transmises selon un mode mendélien. Elles se caractérisent par des accès fébriles récurrents spontanément résolutifs accompagnés d'une inflammation systémique et d'une atteinte des séreuses. La complication la plus grave réside dans le risque de survenue d'une amylose inflammatoire, essentiellement rénale. Le diagnostic clinique des FRH est difficile à établir du fait d'une part d'une grande variabilité inter et intra familiale des phénotypes complexes qui peuvent combiner des signes évocateurs de plusieurs FRH, et d'autre part de l'absence, dans la majorité des cas, de critères objectifs de diagnostic. Alors que le diagnostic de certitude repose essentiellement sur l'identification de défauts moléculaires dans des gènes de l'immunité innée (comme NLRP3, NLRP12, ou MEFV), ces mutations ne rendent compte de la pathologie que chez moins de 30% des cas. Le retentissement fonctionnel de ces variations de séquence, qui sont essentiellement des mutations faux-sens, souvent conservatives, n'a été étudié que dans des lignées cellulaires qui n'expriment pas plusieurs acteurs clés de l'inflammasome, un complexe multiprotéique activé chez les patients présentant une FRH. Au cours de cette thèse, nous avons développé un modèle cellulaire pertinent des FRH à partir de cultures primaires de macrophages humains, dans le but d'étudier les conséquences fonctionnelles des mutations identifiées dans les gènes de FRH et de caractériser les réseaux moléculaires auxquels appartiennent les protéines codées par ces gènes. En parallèle, nous avons cherché à identifier de nouveaux gènes impliqués dans les FRHHereditary recurrent fevers (HRF) define a group of auto-inflammatory diseases transmitted in a Mendelian fashion. They are characterized by recurrent episodes of fever spontaneously resolved, accompanied by systemic inflammation, usually revealed by sterile arthritis, peritonitis, and/or pleurisy. The most serious complication in HRFs is the risk of inflammatory amyloidosis, mainly renal. The clinical diagnosis of HRF is challenging due on the one hand to the inter- and intra- family variability and to complex phenotypes, which combine signs suggestive of different HRFs, and on the other hand, to the absence of objective diagnostic criteria in the majority of cases. While definitive diagnosis is mainly based on the identification of molecular defects in genes of innate immunity (as NLRP3, NLRP12 or MEFV), mutations in these genes account for the pathology in a limited number of patients (30% of cases in our experience). The functional impact of these sequence variations, which are mainly conserved missense mutations, has been studied mainly in heterologous cell lines that do not express several key players of the inflammasome, a multiprotein complex active in patients with HRF. In this thesis, we developed a physiologically relevant cell model of HRF using primary human macrophages in order to assess the functional consequences of the disease-causing mutations and to characterize the molecular networks to which the involved proteins belong. In parallel, we sought to identify novel genes involved in HRF
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Pollard, Patrick John. "Genetic and functional analysis of tumourigenesis in hereditary leiomyomatosis and renal cell cancer and hereditary paragangliomatosis syndromes." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1446046/.
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Hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL) are familial cancer syndromes, caused by germline mutations in genes encoding the Tricarboxylic Acid Cycle (TCAC) enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) respectively. Both FH and SDH function as tumour-suppressor genes and the conditions are inherited as autosomal dominant traits. Germline FH mutations predispose individuals to develop benign smooth muscle tumours of the skin and uterus (leiomyomas) and renal carcinoma, whilst individuals with mutations in SDHB, -C, and -D develop paragangliomas and phaeochromocytomas. In order to study the genetic and functional consequences of FH and SDH mutations, and to elucidate mechanisms of tumourigenesis, which are poorly understood, I have undertaken a comprehensive analysis of tumours from both HPGL and HLRCC patients, using gene and protein expression analysis, metabolomic profiling and cytogenetic analysis of HPGL tumours. Tumours from both syndromes over- express hypoxia-inducible factor-alpha (HIFla), the central signalling protein in hypoxia, and HIFIa-target genes including vascular endothelial growth factor (VEGF) and Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3). HLRCC and HPGL tumours accumulate the TCAC intermediates succinate and fumarate which have been shown to up-regulate HIFla in vitro by inhibiting the prolyl hydroxylases (PHD) that target HIFlct for proteosomal degradation. Therefore, 'pseudo-hypoxia' - the constitutive expression of HIFla in normoxic conditions - is likely to contribute largely to the tumourigenesis of HLRCC and HPGL and is most likely to occur as a direct result of accumulation of TCAC intermediates and PHD inhibition. To further investigate the tumourigenesis of HLRCC, I have successfully created a conditional Fhl (the mouse homologue of human FH) mouse knockout which causes hypertrophy when targeted to smooth muscle. I aim to create further temporal and tissue specific knockouts of Fhl, and if these mice develop tumours provide a model of HLRCC for the testing of anti-cancer drugs and therapies.
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Nizialek, Emily A. "KLLN as Tumor Suppressor in Cowden Syndrome and Sporadic Breast Cancers." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1409778932.
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Martin, P. (Paula). "Type IV collagen:characterization of the COL4A5 gene, mutations in Alport syndrome, and autoantibodies in Alport and Goodpasture syndromes." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256867.
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Abstract
Type IV collagen is only found in basement membranes, where
it is the major structural component, providing a framework for
the binding of other basement membrane components and a substratum for
cells. The type IV collagen molecule is triple-helical and composed
of three a chains which exist as six distinct forms (α1 - α6).
Abnormalities in this basement membrane collagen structure and function
are connected to both inherited and acquired diseases.
Alport syndrome is a hereditary kidney disease associated
with extrarenal complications, such as sensorineural deafness and
eye abnormalities. The disease is caused by mutations in the COL4A3, COL4A4
and COL4A5 genes, coding for the type IV collagen α3, α4
and α5 chain genes, respectively. About 85% of
the Alport syndrome cases are X-linked dominant, caused by mutations in
the COL4A5 gene. In order to develop a basis for automated mutation
analysis of the COL4A5 gene, previously unknown intron sequences
flanking exons 2 and 37 were determined. Intron sequences flanking
the other 49 exons were expanded from 35 to 190, and additionally,
two novel 9 bp exons (exons 41A and 41B) were characterized in the
large intron 41. In addition to optimization of the PCR amplification
and sequencing conditions for all 51 exons and exon flanking sequences, optimization
for the 820 bp promoter region and for the two novel exons was performed
as well. Mutations were found in 79 unrelated patients of the 107
studied. This gives a high mutation detection rate of almost 75% in
comparison with 50%, at its best, in other extensive mutation
analyses of the COL4A5 gene using SSCP analysis. None of the mutations
involved the promoter region or exons 41A and 41B.
Circulating antibodies against basement membrane components
have been recognized in some autoimmune diseases. Goodpasture syndrome
is a rare autoimmune disease characterized by progressive glomerulonephritis
and pulmonary hemorrhage. The target of the antibodies in this disease
has been shown to be the noncollagenous NC1 domain of type IV collagen α3
chain. For unknown reasons, a minority of Alport syndrome patients
also develops antibodies against α3 and α5 chains
after renal transplantation with manifestation of severe anti-GBM
disease. In order to investigate the antibodies both in Goodpasture
and Alport syndrome, the NC1 domains of all six type IV collagen
chains were produced as recombinant proteins in bacterial and mammalian
expression systems, and an ELISA method was developed for antibody
detection. Antibodies were found in both syndromes, interestingly
also in Alport syndrome patients without the anti-GBM disease.
The results of this work have a significant clinical value
by providing for the first time complete, effective DNA-based analysis
of all exon/intron and promoter regions of the COL4A5 gene
in Alport syndrome.
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Green, Jane S. "Development, implementation and evaluation of clinical and genetic screening programs for hereditary tumour syndromes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25771.pdf.
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Santos, João Paulo Franco dos. "Prevalência de critérios para avaliação genética em pacientes com câncer de mama atendidos no hospital universitário de Santa Maria." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/143202.
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Objetivo: Até 10% dos casos de câncer de mama estão associados com uma síndrome genética de predisposição ao câncer. A identificação de possíveis portadores dessas síndromes e o consequente encaminhamento para aconselhamento genético permitem a adoção de estratégias direcionadas de prevenção e rastreamento capazes de diminuir morbidade e mortalidade. O objetivo do presente estudo foi avaliar a proporção de pacientes com câncer de mama atendidos no Hospital Universitário de Santa Maria (HUSM) que necessitariam ser encaminhados para avaliação genética. Métodos: Pacientes com câncer de mama que iniciaram tratamento oncológico no HUSM durante o ano de 2014 foram considerados elegíveis. Uma entrevista foi conduzida com cada paciente para coleta de dados e exame físico dirigido. O questionário FSH-7 (Family Story Screening 7) e os critérios do NCCN (National Comprehensive Cancer Network) foram utilizados para identificar os pacientes que deveriam ser encaminhados para avaliação genética. Estes pacientes foram então avaliados quanto à indicação de teste genético - de acordo com as recomendações do NCCN para teste genético – e à probabilidade de mutações nos genes BRCA1 e BRCA2 através de modelos de predição de risco (BOADICEA, Penn II, sistema de escore de Manchester e tabelas da Myriad). Resultados: Dentre os 114 participantes do estudo, 65 (57%) preenchiam critérios de encaminhamento para avaliação genética de acordo com as diretrizes do NCCN. O questionário FHS-7 apresentou uma sensibilidade de 90% para identificar estes pacientes, com uma especificidade de 85%. A presença de história pessoal ou familiar de câncer de mama antes dos 50 anos foi o critério mais comum para indicar avaliação genética. Em relação aos testes genéticos, 52 pacientes (45%) deveriam ser testados para mutações nos genes BRCA1 e BRCA2 e 4 pacientes (3,5%) possuíam indicação de teste para mutações em TP53, de acordo com as recomendações do NCCN. Utilizando os modelos de predição de risco, 10,2% a 57,1% dos pacientes apresentavam uma probabilidade ≥ 10% de mutações em BRCA1 ou BRCA2. Conclusão: Este estudo revelou que a maioria dos pacientes com câncer de mama atendidos no HUSM possui indicação de encaminhamento para avaliação genética. A utilização de um questionário simples e rápido poderia identificar 90% destes pacientes.Objective: Up to 10% of breast cancers are associated with a hereditary cancer syndrome. The identification of possible carriers of these syndromes and the subsequent referral for genetic counselling allow the adoption of tailored screening and prevention strategies capable of reducing morbidity and mortality. The aim of this study is to assess the proportion of patients with breast cancer treated at the University Hospital of Santa Maria (HUSM) that would need to be referred for genetic evaluation. Methods: Breast cancer patients who began cancer treatment at HUSM during the year 2014 were eligible. An interview was conducted with each patient for data collection and targeted physical examination. The FSH-7 (Family Story Screening 7) questionnaire and the NCCN (National Comprehensive Cancer Network) criteria were used to identify patients who should be referred for genetic evaluation. Then these patients were assessed for genetic testing criteria - according to the NCCN recommendations for genetic testing - and the likelihood of BRCA1 and BRCA2 mutations through risk prediction models (BOADICEA, Penn II, Manchester score system and Myriad tables). Results: Among the 114 study participants, 65 (57%) meet referral criteria for genetic evaluation according to the NCCN guidelines. The FHS-7 questionnaire showed a sensitivity of 90% to identify such patients with a specificity of 85%. The presence of personal or family history of breast cancer before age 50 was the most common criteria to indicate genetic evaluation. With respect to genetic testing, 52 patients (45%) should be tested for BRCA1 and BRCA2 mutations and 4 patients (3.5%) had test indication for TP53 mutations in accordance with the recommendations of the NCCN. Using risk prediction models, 10.2% to 57.1% of patients had a BRCA1 or BRCA2 mutations probability ≥ 10%. Conclusion: This study showed that most of the patients with breast cancer treated at HUSM have referral indication for genetic evaluation. The use of a fast and simple questionnaire could identify 90% of these patients.
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Gauerke, Jennifer Leigh. "Genetic Evaluation of Patients and Families with Concern for Hereditary Tumor Syndromes within the OSU James Multidisciplinary Neuroendocrine/Thyroid Cancer." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555086532080802.
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Yehia, Lamis. "Novel Role of SEC23B as a Cancer Susceptibility Gene in Cowden Syndrome and Apparently Sporadic Thyroid Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1512647647672648.
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Rossanese, Lillian Barbosa de Queiroz 1980. "Estudo de mutações no gene APC em famílias com polipose adenomatosa familiar = APC germile mutations in families with familal adenomatous polyposis." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313231.
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Orientador: Carmen Silvia BertuzzoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Mutações germinativas no gene APC (Polipose adenomatosa coli) são responsáveis pela ocorrência de polipose adenomatosa familiar (PAF). Mutações somáticas levam à transformação maligna de adenomas. O objetivo desse trabalho foi identificar mutações germinativas no gene APC. No presente estudo, 20 pacientes com PAF foram estudados. A determinação das mutações germinativas no APC foi realizada por meio de sequenciamento, e as mutações foram comparadas com marcadores clínicos (sexo, idade no momento do diagnóstico, tabagismo, estádio TNM, classificação Coller-Astler e o grau de diferenciação do adenocarcinoma). Os dados foram comparados por meio do programa SPSS , com o teste de Fisher e teste de ?2 , considerando ? = 0,05. De acordo com os principais resultados da nossa amostra, 16 alelos com mutações deletérias (80 % dos pacientes) foram identificados, enquanto 7 (35%) pacientes não tinham mutações deletérias. Houve um predomínio de mutações nonsense (45% dos pacientes) e de mutações frameshift (20% dos pacientes). Não houve significância estatística entre as mutações germinativas identificadas e as variáveis clínicas consideradas em nosso estudo. Apenas a fase TNM foi associada com a presença de mutações deletérias. Os portadores com mutações deletérias tinha uma OR , 0,086 ( IC = 0,001-0,984 ); TNM I + II em comparação com III + IV , quando comparado com os pacientes sem mutações deletérias identificados. Neste estudo, demonstramos a heterogeneidade molecular de mutações germinativas no APC em portadores de PAF e a dificuldade para realizar diagnóstico molecular em uma população brasileira
Abstract: Adenomatous polyposis coli (APC) germline mutations are responsible for the occurrence of familial adenomatous polyposis (FAP). Somatic mutations lead to malignant transformation of adenomas. In this context, considering the significance of APC germline mutations in FAP, we aimed to identify APC germline mutations. In the present study, 20 FAP patients were enrolled. The determination of APC germline mutations was performed using sequencing, and the mutations were compared with clinical markers (gender, age at diagnosis, smoking habits, TNM stage, Astler-Coller stage, degree of differentiation of adenocarcinoma). The data were compared using the SPSS program, with the Fisher's exact test and ?2 test, considering ?=0.05. According to the main results in our sample, 16 alleles with deleterious mutations (80% of the patients) were identified while 7 (35%) patients had no deleterious mutations. There was a predominance of nonsense (45% of the patients) and frameshift (20% of the patients) mutations. There was no statistical significance between the APC germline mutations identified and the clinical variables considered in our study. Only TNM stage was associated with the presence of deleterious mutations. Patients with deleterious mutations had an OR, 0.086 (IC=0.001-0.984); TNM stage I + II in comparison with III + IV, when compared with the patients with no deleterious mutations identified. In this context, as a conclusion, we demonstrated the molecular heterogeneity of APC germline mutations in FAP and the difficulty to perform molecular diagnostics in a Brazilian population, considering the admixed population analyzed
Doutorado
Clinica Medica
Doutora em Ciências
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Guindalini, Rodrigo Santa Cruz. "Identificação de variantes germinativas no gene E-caderina / CDH1 e de fatores ambientais de risco em pacientes jovens portadores de câncer gástrico." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-04112016-112630/.
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Introdução: Câncer gástrico é uma doença multifatorial influenciada por fatores externos e hereditários. Embora a síndrome do câncer gástrico difuso hereditário causada por mutações germinativas no gene CDHl seja uma condição rara, sua influência sobre a incidência de câncer gástrico no Brasil, que é considerado um país de alta incidência desta neoplasia, é desconhecida. Objetivos: Avaliar a frequência de variantes germinativas em CDHl e os hábitos de dieta/estilo de vida em pacientes diagnosticados câncer gástrico com idade precoce «55 anos) no Brasil. Metodologia: De outubro de 2013 a agosto 2015, foram recrutados 88 pacientes consecutivos e não aparentados diagnosticados com câncer gástrico em idade precoce em um hospital público brasileiro. Todos os éxons e regiões intrônicas flanqueadoras do CDHl foram sequenciados. Os hábitos de dieta/estilo de vida dos pacientes com câncer gástrico em idade precoce foram comparados com informações sobre os hábitos da população armazenados em bancos de dados populacionais brasileiros. Resultados: Dos 88 pacientes, 51,1% eram do sexo feminino e a média de idade no momento do diagnóstico do câncer era de 39 anos (variação, 20-55); 23% relataram história familiar de câncer gástrico em parentes de primeiro ou de segundo. A maioria dos tumores era do tipo difuso (74%), pouco diferenciado (74%) e localizava-se no terço médio ou distal do estômago (67%). No total, 24 variantes germinativas foram detectadas: 3 (12.5%) benignas, 17 (70.8%) provavelmente benignas e 4 (16.7%) variantes de significado clínico incerto (VSI). Todas as VSI são mutações missense e nunca foram relatadas previamente na literatura: c.313T> A, c.387G> T, c.1676G> A e c.1806C> A. Os pacientes com câncer gástrico diagnosticados em idade precoce apresentaram maior consumo de carne vermelha (OR: 2.591, IC 95%: 1.371-4.894) e carne processada (OR: 3.093, IC 95%: 1.591- 6.009) em comparação com os hábitos alimentares da população brasileira. Conclusão: De acordo com o nosso conhecimento, esta é a maior série investigando a contribuição de mutações germinativas de CDHl em pacientes diagnosticados com câncer gástrico em idade precoce na América Latina. Para um país considerado de alta incidência, a frequência encontrada de variantes germinativas em CDHl foi maior do que o esperado; 4 novas mutações missense foram identificadas e mais estudos são necessários para confirmar a patogenicidade dessas variantes. Fatores de risco modificáveis, como o consumo de carne vermelha e/ou de carne processada podem ter contribuído para o desenvolvimento de câncer gástrico em idade precoce na população estudadaIntroduction: Gastric cancer is a multifactorial disease influenced by inherited and noninherited factors. Although hereditary diffuse gastric cancer syndrome caused by germline mutation in CDHl is arare condition its contribution to gastric cancer burden in Brazil, which is considered a high-incidence country for this neoplasia, is unknown. Objectives: To evaluate the frequency of CDHl germline variants and the dietjlifestyle habits in early-onset gastric cancer (EOGC, < 55 years old) patients in Brazil. Methodology: From October 2013 to August 2015, a total of 88 unrelated and consecutive patients attending a Brazilian public hospital with EOGC were enrolled. Ali CDHl exons and intronic boundaries were sequenced. The dietjlifestyle habits of EOGC patients have been compared to Brazilian population data bases. Results: Of 88 patients, 51.1% were female and the mean age at gastric cancer diagnosis was 39 years (range 20-55); 23% reported family history of gastric cancer in first- or second-degree rei atives. The majority of the tumors were diffuse (74%), poorly differentiated (74%), and located in the middle and distal-third of the stomach (67%). In total, 24 germline variants were detected: 3 (12.5%) benign, 17 (70.8%) likely benign, and 4 (16.7%) variants of unknown significance (VUS). Ali VUS were missense novel mutations: c.313T > A, c.387G > T, c.1676G > A, and c. 1806C > A. EOGC patients had ahigher red (OR: 2.591, 95% CI: 1.371-4.894) and processed (OR: 3.093, 95% CI: 1.591-6.009) meat intake compared to eating habits of the Brazilian population. Conclusion: To our knowledge, this is the largest series investigating the contribution of CDHl germline mutations in EOGC cancer in Latin America. For a high-incidence country, the incidence of CDHl germline variants was higher than expected; 4 novel CDHl missense mutations were identified and further studies are warranted to confirm their pathogenicity. Modifiable risk factors, such as the consumption of red and/or processed meat may have contributed to early- onset gastric cancer development in our studied population
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Karppinen, S. M. (Sanna-Maria). "The role of BACH1, BARD1 and TOPBP1 genes in familial breast cancer." Doctoral thesis, University of Oulu, 2009. http://urn.fi/urn:isbn:9789514291593.
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Abstract
Approximately 5–10% of all breast cancer cases are estimated to result from a hereditary predisposition to the disease. Currently no more than 25–30% of these familial cases can be explained by mutations in the known susceptibility genes, BRCA1 and BRCA2 being the major ones. Additional predisposing genes are therefore likely to be discovered. This study evaluates whether germline alterations in three BRCA1-associated genes, BACH1 (i.e. BRIP1/FANCJ), BARD1 and TOPBP1, contribute to familial breast cancer.
Altogether 214 Finnish patients having breast and/or ovarian cancer were analysed for germline mutations in the BACH1 gene. Nine alterations were observed, four of which located in the protein-encoding region. The previously unidentified Pro1034Leu was considered a possible cancer-associated alteration as it appeared with two-fold higher frequency among cancer cases compared to controls. All the other observed alterations were classified as harmless polymorphisms.
Mutation analysis of the BARD1 gene among 126 Finnish patients having family history of breast and/or ovarian cancer revealed seven alterations in the protein-encoding region. The Cys557Ser alteration was seen at an elevated frequency among familial cancer cases compared to controls (p = 0.005, odds ratio [OR] 4.2, 95% confidence interval [CI] 1.7–10.7). The other alterations appeared to be harmless polymorphisms. To evaluate further the possible effect of Cys557Ser on cancer risk, a large case-control study was performed, consisting of 3,956 cancer patients from the Nordic countries. The highest prevalence of Cys557Ser was found among breast and ovarian cancer patients from BRCA1/BRCA2 mutation-negative families (p < 0.001, OR 2.6, 95% CI 1.7–4.0). In contrast, no significant association with male breast cancer, ovarian, colorectal or prostate cancer was observed.
The current study is the first evaluating the role of TOPBP1 mutations in familial cancer predisposition. The analysis of 125 Finnish patients having breast and/or ovarian cancer revealed one putative pathogenic alteration. The commonly occurring Arg309Cys allele was observed at a significantly higher frequency among familial cancer cases compared to controls (p = 0.002, OR 2.4, 95% CI 1.3–4.2). The other 18 alterations observed were classified as harmless polymorphisms.
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Bartos, Daniel C. "Mechanistic Basis for Atrial and Ventricular Arrhythmias Caused by KCNQ1 Mutations." UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/8.
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Cardiac arrhythmias are caused by a disruption of the normal initiation or propagation of electrical impulses in the heart. Hundreds of mutations in genes encoding ion channels or ion channel regulatory proteins are linked to congenital arrhythmia syndromes that increase the risk for sudden cardiac death. This dissertation focuses on how mutations in a gene (KCNQ1) that encodes a voltage-gated K+ ion channel (Kv7.1) can disrupt proper channel function and lead to abnormal repolarization of atrial and ventricular cardiomyocytes.
In the heart, Kv7.1 coassembles with a regulatory protein to conduct the slowly activating delayed rectifier K+ current (IKs). Loss-of-function KCNQ1 mutations are linked to type 1 long QT syndrome (LQT1), and typically decrease IKs, which can lead to ventricular action potential (AP) prolongation. In patients, LQT1 is often characterized by an abnormally long corrected QT (QTc) interval on an electrocardiogram (ECG), and increases the risk for polymorphic ventricular tachycardias.
KCNQ1 mutations are also linked to atrial fibrillation (AF), but cause a gain-of-function phenotype that increases IKs. Surprisingly, patients diagnosed with both LQT1 and AF are increasingly identified as genotype positive for a KCNQ1 mutation. The first aim of this dissertation was to determine a unique functional phenotype of KCNQ1 mutations linked to both arrhythmia syndromes by functional analyses via the whole-cell patch clamp technique in HEK293 cells.
A proportion of patients with LQT1-linked KCNQ1 mutations do not have abnormal QTc prolongation known as latent LQT1. Interestingly, exercise can reveal abnormal QTc prolongation in these patients. During exercise, beta-adrenergic activation stimulates PKA to phosphorylate Kv7.1, causing an increase in IKs to prevent ventricular AP prolongation. Therefore, the second aim of this dissertation was to determine a molecular mechanism of latent LQT1 through functional analyses in HEK293 cells while incorporating pharmacological and phosphomimetic approaches to study PKA regulation of mutant Kv7.1 channels.
The findings in this dissertation provide new insight into how KCNQ1 mutations disrupt the function of Kv7.1 in a basal condition or during beta-adrenergic activation. Also, this dissertation suggests these approaches will improve patient management by identifying mutation specific risk factors for patients with KCNQ1 mutations.
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Vidal, João Paulo Castello Branco. "Avaliação das alterações do gene VHL nos carcinomas renais de células claras associados à síndrome de von Hippel-Lindau." Universidade do Estado do Rio de Janeiro, 2010. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=1925.
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A Síndrome de von Hippel-Lindau é uma doença hereditária multissistêmica, causada por mutações germinativas no gene VHL que predispõe o portador a manifestações benignas e malignas em diversos órgãos. Entre esses eventos, o carcinoma de células claras renais (CRC) é o de pior prognóstico, com uma penetração média de 25% e sendo a principal causa de morte nestes pacientes. Os CRCs são tumores agressivos, pouco responsivos à quimioterapia e imunoterapia, e muitas vezes são diagnosticados em estágios avançados. Podem estar associados a síndromes hereditárias como o VHL ou apresentar a forma esporádica. Caracteristicamente, o CRC é provocado pela inativação dos dois alelos do gene VHL. Nos casos associados ao VHL, um alelo do gene VHL sofre uma mutação germinativa e um segundo evento mutacional somático nas células do tumor. Por outro lado, na forma esporádica, o CRC é resultado de dois eventos somáticos adquiridos, que incluem uma combinação de metilação do promotor, mutações pontuais que afetam a sequência de leitura aberta (ORF) e rearranjos cromossômicos, principalmente perda de heterozigosidade (LOH). Embora os eventos somáticos nos CRCs esporádicos já tenham sido explorados em outros estudos, os mecanismos de inativação somáticos do gene VHL nos CRCs associados à síndrome ainda não foram bem descritos. Este estudo avaliou os eventos somáticos no gene VHL em CRCs retirados em procedimentos cirúrgicos de pacientes portadores da síndrome. Os eventos somáticos em vários tumores de um mesmo paciente foram comparados a fim de verificarmos se essas mutações são independentes e não clonais. Oito pacientes com amostras CRCs previamente armazenadas no BNT tiveram sua mutação germinativa no gene VHL caracterizada por sequenciamento ou MLPA. Todas as amostras foram submetidas a uma revisão da patologia e macrodissecadas sempre que necessário. Para a análise das manifestações somáticas do gene VHL, o DNA foi extraído de 30 CRCs conservados em RNA latter ou formaldeído (parafina). As amostras foram analisadas quanto à metilação da região promotora do gene pelo método MS-PCR e para mutações pontuais por sequenciamento. Fomos capazes de detectar a mutação somática em 25 dos 30 tumores, incluindo uma mutação pontual e dois tumores diferentes de um mesmo paciente, nenhuma microdeleção e 23 grandes deleções. Em contraste com a literatura, nenhum dos tumores apresentou metilação no promotor do VHL. Devido ao grande número de achados LOH e da resolução limitada da técnica de MLPA para avaliar a extensão dos rearranjos cromossômicos em 3p, não foi possível concluir a análise de clonalidade dos tumores. Um estudo exploratório para caracterizar ganhos e perdas genômicas utilizando a técnica CNV array está em andamento em nosso laboratório.The von Hippel-Lindau syndrome (VHL) is a multissystemic hereditary disease, caused by germline mutations in the VHL gene that predisposes the carrier to benign and malignant manifestations in different organs. Among these events, the clear cell renal carcinoma (RCC) is the most fearful, with an average penetration of 25% being the leading cause of death in these patients. RCCs are aggressive tumors, poorly responsive to chemo- and immunotherapy that are often diagnosed in advanced stages. They can be associated with hereditary syndromes such as VHL or present in a sporadic form. Characteristically, RCCs carrier the inactivation of the two alleles of VHL gene. In cases associated with VHL, one allele of the VHL gene is mutated in the germline, and the second mutational event occurs in the somatic cells of the tumor. On the other hand, in the sporadic form, RCCs results of two acquired somatic events, which includes a combination of methylation of the promoter, point mutations affecting the ORF, and rearrangements mainly loss of heterozigosity (LOH). Although somatic events in sporadic RCC have been explored before by others, the mechanisms of somatic VHL gene inactivation in VHL-associated RCCs have been poorly characterized. This study evaluated the somatic mutational events in the VHL gene of RCCs removed from VHL patients in therapeutic surgical procedures. The somatic events in multiple tumors from the same patient were compared in order to analyze whether these mutations are independent and not clonal. Eight patients with RCCs samples previously stored at BNT had their germline VHL gene mutation characterized by sequencing or MLPA. All samples were submitted to a pathology review and macrodissected whenever necessary. For the analysis of somatic events of VHL gene, DNA from 30 RCCs were extracted from either RNA later or archival formalin-fixed, paraffin-embedded tissue sections. Samples were analyzed for VHL gene promoter methylation by MS-PCR, and for point mutation in the coding DNA by sequencing. We were able to detect the somatic mutation in 25 of the 30 tumors, including one point mutations in two different tumors of the same patient, no micro-deletions, and 23 large deletions. In contrast to the literature, none of the tumors have shown methylation on the VHL promoter. Because of the large number of LOH findings, and the limited resolution of MLPA to evaluate the extension of 3p chromosomal rearrangements, we could not conclude the analysis of tumor clonality. An exploratory study to characterize genomic gains and losses using CNV-array technique are ongoing in our laboratory.
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Rodríguez, Balada Marta. "Aplicació de tècniques òmiques per a la millora del diagnòstic en la síndrome de càncer de mama i ovari hereditari." Doctoral thesis, Universitat Rovira i Virgili, 2020. http://hdl.handle.net/10803/670307.
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La síndrome de càncer de mama i ovari hereditari és una de les síndromes de càncer hereditari més freqüents. Al
voltant del 5-10% dels casos s’associen a variants patogèniques en els gens BRCA1 i BRCA2. La identificació
d’aquestes alteracions és important per a realitzar un assessorament genètic que ajudi a prendre decisions mèdiques
basades en l’avaluació del risc individual. En l’estudi genètic d’aquesta síndrome, també s’identifiquen variants de
significat incert, que dificulten el procés d’assessorament genètic. Per a poder classificar aquestes variants s’utilitzen
principalment anàlisis multifactorials que inclouen l’estudi de la cosegregació de la variant, la freqüència poblacional i
l’anàlisi del procés d’empalmament. Tot i això, continuen quedant moltes variants sense categoritzar i per això calen
altres eines per a identificar i classificar aquestes variants així com estudiar altres gens que ens puguin explicar la
causa hereditària de la malaltia. Per tot això, mitjançant els diferents estudis d’aquesta tesi doctoral basats en diferents
tècniques òmiques, s’ha pogut classificar algunes variants mitjançant la combinació de freqüència poblacional, anàlisi
in silico i estudi de l’ARN. A més a més, s’ha descartat la hipermetilació del promotor dels gens BRCA1 i BRCA2 com
a mecanisme hereditari de silenciament gènic en aquesta síndrome, i s’han identificat altres gens, principalment el gen
PALB2, com a gens a incloure en l’estudi d’aquesta síndrome. Finalment s’ha fet un estudi basat en metabolòmica que
ha permès identificar una empremta característica amb capacitat predictora del fenotip BRCA-like de càncer de mama.El síndrome de cáncer de mama y ovario hereditario es uno de los síndromes de cáncer hereditario más frecuentes. Alrededor del 5-10% de los casos son portadores de variantes patogénicas en los genes BRCA1 y BRCA2. La identificación de éstas es importante para realizar un asesoramiento genético que ayude en la toma de decisiones médicas basadas en la evaluación del riesgo individual. En su estudio genético, también se identifican variantes de significado incierto, que dificultan el proceso de asesoramiento genético. Para clasificarlas se usan principalmente análisis multifactoriales que incluyen el estudio de la cosegregación de la variante, frecuencia poblacional y análisis del proceso de splicing. No obstante, siguen quedando muchas variantes sin categorizar, por lo que se necesitan otras herramientas para identificar y clasificarlas y para estudiar otros genes que puedan explicar la causa hereditaria de la enfermedad. Mediante los diferentes estudios que conforman esta tesis doctoral, basados en diferentes técnicas ómicas, se han podido clasificar algunas variantes mediante la combinación de frecuencias poblacionales, análisis in silico y estudio del ARN. Además, se ha descartado la hipermetilación del promotor de los BRCA1 y BRCA2 como un mecanismo hereditario de silenciamiento génico en este síndrome, y se han identificado otros genes a incluir en el análisis de el síndrome. Finalmente, se ha llevado a cabo un estudio basado en metabolómica que ha permitido identificar una huella con capacidad predictiva del fenotipo BRCA-like de cáncer de mama.
Hereditary breast and ovarian cancer syndrome is one of the most common hereditary cancer syndromes. At least 5-10% of cases are associated with pathogenic variants in the BRCA1 and BRCA2 genes. The identification of these alterations is important to carry out genetic counselling that helps to make medical decisions based on the assessment of the individual risk. In the mutational study, variants of uncertain significance are also identified, which make the process of genetic counselling difficult. To classify them, strategies based on multifactorial analysis are used, which include as cosegregation analysis of the variant, population frequency, as well as the mRNA splicing. However, there are still many variants that cannot be categorized. That’s the reason why other methods are needed to identify and classify them, as well as to study other genes that can explain the hereditary cause of cancer. Therefore, the studies included in this doctoral thesis, based on different omics techniques, allow us to classify some unclassified variants by means of a combination of population frequency, in silico analysis and mRNA study. Moreover, the hypermethylation of the promoter of the BRCA1 and BRCA2 genes has been ruled out as a hereditary mechanism of genetic silencing in this syndrome, and other genes have been identified as genes to be included in the study of this syndrome. Finally, a metabolomics-based study has been carried out to identify a characteristic fingerprint with the ability to predict the BRCA-like phenotype of breast cancer.
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Nelson, Andrew Cook. "Molecular regulation of the breast and ovarian tumor suppressors BRCA1 and BRCA2 /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Find full textAbstract:
Thesis (Ph.D. in Experimental Pathology, Program in Cancer Biology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 144-158). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Boye, Eileen. "Molecular characterisation of mutations in X-linked Alport syndrome." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283131.
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Huusko, P. (Pia). "Predisposing genes in hereditary breast and ovarian cancer." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254422.
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Abstract
In the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland. In the 15 Turkish cancer families studied, 5382insC and 5622C→T were detected in BRCA1, and 3414delTCAG in BRCA2. The novel 3414del4 mutation was found in a family with a case of male breast cancer.
In order to determine their ages and origin, 9 recurrent Finnish BRCA1 and BRCA2 mutations were studied further as regards haplotype conservation. Common origins approximately 18–80 generations (400–1600 years) ago were demonstrated for all studied mutations by partial haplotype sharing. The majority of the mutations showed geographical clustering, supporting the theory of regional founder effects. Four of the nine mutations are unique for Finland, whereas five have also been seen elsewhere. Mutations in the 5' end of BRCA1 tend to predispose individuals to ovarian cancer and those found in the 3' end to breast cancer. The age of ovarian cancer onset was significantly lower for BRCA1 (51 years) than for BRCA2 mutation carriers (61 years).
Germline TP53 mutations were sought in the Finnish breast cancer families found to be negative after BRCA1 and BRCA2 screening but who exhibited some phenotypic features of the Li-Fraumeni syndrome. The Asn235Ser was found in a family displaying Li-Fraumeni syndrome phenotype and the Tyr220Cys in a family with a milder Li-Fraumeni-like phenotype. The nature of both mutations as cancer-predisposing alterations was supported by means of loss of heterozygosity (LOH) and p53 immunohistochemistry studies.
Regional clustering of BRCA1 and BRCA2 founder mutations enables targeted genetic tests including especially those mutations characteristic of the birthplace of each patient. Additional genes are likely to explain a large proportion of the inherited susceptibility to breast cancer in particular. Germline TP53 mutations are expected to be found in the breast cancer families with other clinical features seen in the Li-Fraumeni syndrome.
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Viana, Danilo Vilela 1975. "Caracterização genético-clínica dos quadros com mutações bialélicas nos genes MMR." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308577.
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Orientador: Carmen Silvia BertuzzoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Há muito tempo reconhece-se a importância de fatores hereditários na oncogênese. Dentre os genes associados ao câncer, um importante grupo é formado por aqueles direta ou indiretamente relacionados ao reparo do DNA, entre os quais está um grupo de genes pertencentes ao sistema de reparo de erros de pareamento de bases do DNA (mismatch repair - MMR), do qual fazem parte hMLH1, hMSH2, hMSH6 e hPMS2. Quando mutações monoalélicas nesses genes são herdadas, elas são responsáveis pela síndrome de Lynch, que cursa com predisposição ao câncer de cólon e endométrio, entre outros, geralmente na terceira ou quarta década de vida. A ocorrência de câncer na infância ou de tumores hematológicos não é comum na síndrome de Lynch. Nos últimos anos, entretanto, foram relatados diversos casos de pacientes que, na primeira ou segunda década de vida, apresentam tumores de sistema nervoso central, gastrintestinais, hematológicos, alguns deles com manifestações cutâneas semelhantes à neurofibromatose tipo 1. Nesses pacientes, foram identificadas mutações bialélicas nos genes do sistema MMR. O presente estudo propôs-se a analisar os tecidos tumorais de uma série retrospectiva de pacientes de zero a 35 anos de idade (inclusive), com diagnóstico de câncer de sistema nervoso central, visando a identificação de pacientes com mutações bialélicas nos genes do sistema MMR e a caracterização de seu quadro clínico. Teve por objetivos específicos: identificar os casos com instabilidade de microssatélites (MSI); determinar a proporção de tumores instáveis e o genótipo para os genes do sistema MMR nos casos que foram instáveis; correlacionar as mutações encontradas com o fenótipo e história familial. Um total de 79 pacientes foram incluídos no estudo. O diagnóstico era de glioma em 42 e meduloblastoma em 37. Inicialmente foi realizada a pesquisa de MSI nos tumores de todos os pacientes, seguido de avaliação clínica e coleta de sangue para pesquisa de mutações deletérias nos genes do sistema MMR, naqueles que apresentavam instabilidade. Foi encontrada baixa MSI (MSI-L) em sete casos de glioma e oito casos de meduloblastoma. Esses pacientes foram convocados para avaliação quanto à história clínica, exame físico e história familial. Seis pacientes atenderam ao convite, foram avaliados e tiveram sequenciamento e pesquisa de deleções por meio da técnica de MLPA realizados para os genes hMLH1, hMSH2, hMSH6. Não foram encontradas mutações deletérias em nenhum desses indivíduos. Procedeu-se, ainda, a determinação do intervalo de variação quase monomórfico para a população estudada, após o qual, cinco dos pacientes com diagnóstico de meduloblastoma, originalmente classificados como MSI-L, foram reclassificados como sendo estáveis (MSS). No presente estudo demonstrou-se que 8,3% dos pacientes com diagnóstico de meduloblastoma e 17,5% daqueles com gliomas possuíam MSI-L. A correlação do genótipo com o fenótipo e história familial não pôde ser realizada, visto não terem sido encontradas mutações deletérias. Sugere-se que sejam realizados estudos adicionais, preferencialmente prospectivos, para estabelecer a frequência de mutações nos genes do sistema MMR em pacientes pediátricos e adultos jovens com tumores de sistema nervoso central e instabilidade de microssatélites, uma questão importante para o aconselhamento genético, e, possivelmente, para implantação de uma rotina de rastreamento com pesquisa de MSI nessa população de pacientes
Abstract: Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition disorder characterized by early onset of cancer (mean age, approximately 40-45 years), especially edometrium and/or colorectal cancer in the absence of gastrointestinal polyposis, and which, in addition, shows increased frequency of carcinomas of the ovary, small intestine, ureter, renal pelvis, stomach, among others. Its molecular hallmark is a type of genetic instability known as miscrosattelite instability (MSI) that affects short sequences of DNA repeats (miscrosattelites) found throughout the genome, leading to accumulation of genetic alterations. In LS, Cancer predisposition is due almost exclusively to heterozygous germline mutations in one of the DNA MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6). Childhood cancers and hematological neoplasia generally do not belong to the Lynch tumour spectrum. However, over the past few years there have been reports of children that have presented with the constellation of early onset gastrointestinal cancers, along with features of neurofibromatosis type-1 and/or hematologic malignancies, and/or neurological tumors due to homozygous mutations in the mismatch repair genes. The present study analyzed a retrospective series of central nervous system tissue from patients with 0 to 35 years of age, with the aim to identify biallelic mutations in MMR genes and characterization of its clinical tumor spectrum. The aims of this study were to analyze: the frequency of microsattelite instability in tumors; the genotype and the frequency of germline mutations in MMR genes in patients who had MSI; its correlation to the phenotype and family history. A total of 42 gliomas and 37 medulloblastomas were analyzed. Initially, they were screened for microsatellite instability (MSI), followed by clinical evaluation, family history taking and sequence analysis of DNA obtained from blood lymphocytes. Low MSI (MSI-L) was found in seven gliomas and eight meduloblastomas. These patients were invited for clinical examination, family history taking and blood drawing. Six attended the clinical evaluation and had their sequence analysis done for hMLH1, hMSH2, hMSH6. No deleterious mutations were found among these patients. In adition, the quasi-monomorphic variation range was determined for this population, a important step previously not investigated in Brazilian population, that showed that with the proper values for the target population, 5 from the original MSI-L medulloblastomas were reclassified as stable (MSS). In clonclusion, the present study showed that 8,3% of the medulloblastomas and 17,5% of gliomas had MSI-L. The correlation of the genotype with clinical characteristics and family history could not be done, as no deleterious mutations were found. It was suggestd that new prospective studies are necessary to properly address the issue of the frequency of biallelic mutations in pediatric and young adults patients with MSI-L tumors of the CNS
Doutorado
Genetica Medica
Doutor em Ciências Médicas
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Jefferson, Ashley. "The clinical and molecular features of hereditary nephritis in Northern Ireland." Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318765.
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Bell, Rebecca Jane. "Genetics of x-linked and autosomal recessive hereditary nephropathy in the domestic dog." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2125.
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Patel, Heema. "Mapping of the gene for silver syndrome and gene identification in Troyer syndrome, two forms of hereditary paraplegia." Thesis, St George's, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401635.
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Bergfors, Monica. "Evaluation of Microsatellite Instability Analysis as a Diagnostic Tool to Identify Lynch Syndrome in Endometrial Cancer Patients." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-227772.
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Hereditary endometrial cancer (EC) is a Lynch syndrome (LS) related cancer variant and 2-10% of all EC are hereditary. The aim of this study was to develop a method for analysis of microsatellite instability (MSI) as such analysis would assist in identifying potential LS patients with EC at an early state of their disease, before a possible second cancer is developed in another organ. Twenty-six patients with adenocarcinoma in the endometrium, diagnosed at Uppsala University Hospital in Sweden between 1993 and 2012, were included in the study. Seven of these patients were also diagnosed with LS and the rest were sporadic EC. DNA was extracted from the patients’ formalin-fixed and paraffin-embedded tissues. The extracted DNA was subjected to a multiplex PCR with fluorescently labelled primers and then analysed by using capillary electrophoresis. Of the sporadic EC, 26% was MSI-High, which correlates well with published data. Of the LS patients, 83% was MSI-High. The outcome of this project resulted in that MSI analysis is now a validated and established method used in the process of identifying potential LS among patients with EC.
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Davidson, Ashley Greene. "Characterization of the mutation causative for autosomal recessive hereditary nephropathy in the english cocker spaniel and analysis of gene expression in multiple models of hereditary nephropathy." Thesis, [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1215.
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Dahlqvist, Johanna. "Genetic and Molecular Studies of Two Hereditary Skin Disorders." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-149185.
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Monogenic disorders, i.e., disorders caused by mutations in a single gene, are rare and clinically heterogeneous conditions. Identification of the genetic cause of monogenic traits can bring new insights into molecular pathways and disease mechanisms. The aims of the present study were to identify the mutant genes in two autosomal recessive skin disorders and to characterize the functions of the mutated genes. In order to identify candidate genes for the two disorders whole-genome SNP analysis, homozygosity mapping and gene sequencing were used. Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by extensive scaling and redness of the skin. A subgroup of ARCI patients (n=27) was selected based on specific ultrastructural aberrations in their skin, revealed by electron microscopy. Mutations were identified in the Ichthyin gene in 93% of the selected patients, indicating a strong association between mutant Ichthyin and the specific morphological abnormalities. Ichthyin mRNA levels were shown to increase during keratinocyte differentiation in cells from healthy and affected individuals. Electron microscopy revealed a localization of ichthyin protein to keratins and desmosomes in epidermis. Staining of epidermal lipids identified aberrant lipid aggregates in skin sections of patients with Ichthyin mutations, indicating a role for Ichthyin in epidermal lipid metabolism. In twelve KLICK syndrome patients with ichthyosis, palmoplantar keratoderma and keratotic striae on joints, a single-nucleotide deletion was identified in the 5’ region of the proteasome maturation protein (POMP) gene. The deletion caused an increase in the proportion of POMP transcripts with long 5’ UTR’s in patient keratinocytes. Immunohistochemical analysis of differentiated skin cell layers revealed aberrant expression of POMP, proteasome subunits and the skin protein filaggrin in patients. CHOP expression, associated with endoplasmic reticulum stress, was increased in the same layers. siRNA silencing of POMP in cell cultures reduced proteasome subunit levels and induced expression of CHOP. The results indicate that the mutation in KLICK patients causes POMP and proteasome insufficiency with subsequent cellular stress. This study conclusively contributes to the understanding of epidermal physiology and the pathogenesis of two inherited skin diseases.
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Barrow, Paul. "Hereditary colorectal cancer : registration, screening and prognostic biomarker analysis." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/hereditary-colorectal-cancer-registration-screening-and-prognostic-biomarker-analysis(45d75b71-edc0-4c9f-a381-9ecda92f2fac).html.
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Aims: The purpose of the research was to investigate the benefits of a hereditary colorectal cancer registry in the management of patients and families with Lynch syndrome. In study one, a systematic review was performed to quantify the impact of registration and screening on colorectal cancer (CRC) incidence and mortality, with comparison between familial adenomatous polyposis (FAP) and Lynch syndrome (LS). In study two, a regional Lynch syndrome registry was utilised to evaluate the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) and investigate novel methods for engaging at-risk relatives, including an enhanced role for the general practitioner (GP). In study three, the registry was used to investigate proposed associations between Lynch syndrome and prostate and bladder cancer. In study four, mismatch repair-deficient (dMMR) CRCs from Lynch syndrome patients and randomised-controlled trials (RCTs) were used to evaluate a novel prognostic biomarker, beta-2 microglobulin (B2M). Methods: An electronic database search was conducted to identify studies describing CRC incidence and/or mortality in FAP or LS, with comparison of either: 1) screened and unscreened patients or 2) patients ‘before and after’ establishment of the registry. Using the Manchester regional Lynch syndrome registry database, the uptake of predictive testing and colorectal screening among FDRs was assessed with Kaplan-Meier analysis. Novel strategies for improving engagement were explored via a patient advisory group discussion and a regional primary care questionnaire. Cases of prostate and bladder cancer in male mutation carriers and their male FDRs were identified, and cumulative and relative risks were calculated, using expected rates from cancer registry data. DNA from 350 dMMR CRC specimens from Lynch syndrome patients and RCTs were tested for B2M mutations using Sanger sequencing, and correlated with clinical outcome. Results: 43 studies were included in the systematic review (33 FAP; 10 Lynch). Registry-based screening was associated with a significant reduction in CRC incidence and in Lynch syndrome, CRC-related mortality was negligible in those undergoing surveillance. 242 Lynch syndrome families were recorded on the Manchester Lynch syndrome registry. 329 of 591 (55.7%) eligible FDRs had undergone predictive testing. Uptake was significantly lower in males and younger age groups (<25 yrs). Compliance with colorectal screening was excellent following a mutation positive predictive test but poor in untested individuals (97.3% vs 35.0%). Eight prostate cancers were identified in 821 male LS mutation carriers and male FDRs. MSH2 mutation carriers had a ten-fold increased risk of prostate cancer (RR 10.41; 95%CI 2.80, 26.65) but no association with bladder cancer was identified. 69/286 (24.1%) of dMMR CRCs contained significant B2M mutations. B2M mutations were associated with complete absence of recurrence (0/39) during follow-up in the QUASAR trial (stage II), compared with 14/77 (18.2%) in wild-type B2M (p=0.005). Conclusion: Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in FAP and LS (Level 2a evidence, Grade B recommendation). Funding and managerial support for registries should be made available. Uptake of predictive testing and colorectal screening in Lynch syndrome could be substantially improved, particularly among males and younger age groups, but this requires advances in communication with at-risk relatives. It is unlikely that GPs will actively participate without considerable support from genetics services. A trial of PSA screening in MSH2 mutation carriers from 50 years would be appropriate. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC.
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Marinozzi, Maria Chiara. "Characterization of the complement hereditary and acquired abnormalities in atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB037/document.
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Cederquist, Kristina. "Genetic and epidemiological studies of hereditary colorectal cancer." Doctoral thesis, Umeå : Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-615.
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Ginde, Sadhana Y. "Histochemical and Electron Microscopic Studies on the Skin Disease Keratoderma Hereditaria Mutilans (Vohwinkel's Syndrome)." Connect to online version at OhioLINK ETD Connect to online version at Digital.Maag, 1999. http://hdl.handle.net/1989/4815.
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Chen, Zhiyong. "Rôle physiopathologique des mutations du gène COL4A1 dans le syndrome HANAC (Hereditary Angiopathy, Nephropathy, Aneuryms, and muscle Cramps)." Paris 6, 2011. http://www.theses.fr/2011PA066700.
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Le syndrome HANAC (pour Hereditary Angiopathy, Nephropathy, Aneurysms, and muscle Cramps) est une maladie héréditaire à transmission autosomique dominante due à des mutations du gène COL4A1. Les atteintes systémiques comprennent des anomalies rénales, musculaires et vasculaires. Dans la première partie du travail, quatre nouvelles mutations COL4A1 et une mutation HSP47 ont été identifiés par des études génétiques. Les sept mutations COL4A1 sont localisées dans le domaine CB3(IV) renfermant des sites de liaison pour plusieurs intégrines. La proximité de sept mutations suggère une corrélation phénotype/génotype du syndrome HANAC. L’identification de la première mutation hétérozygote de HSP47 montre que le syndrome HANAC est une maladie génétiquement hétérogène. Dans la deuxième partie, les études faites avec les fibroblastes des patients montrent que la mutation est responsable d’une rétention des trimères de collagène IV, entraînant un stress du RE. Dans la troisième partie, des souris porteuses d’une mutation Col4a1G495V ont été générées pour étudier la physiopathologie du syndrome HANAC. Les mutants développent des anomalies rénales, musculaires et vasculaires. La similarité entre les phénotypes chez la souris et les symptômes chez nos patients permet de valider les souris Col4a1G495V comme modèle d’étude pour ce syndrome. Par ailleurs, les mutants nouveau-nés présentent des défauts podocytaires et les adultes homozygotes développent une papille atrophique, révélant une perturbation de la voie de signalisation d’intégrine alpha3beta1 chez les mutants. La mutation COL4A1 au sein de CB3(IV) est responsable d’un défaut d’interaction entre le collagène IV et les intégrines
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FOIRET, LUC. "Le cancer colique hereditaire non polypoide : le syndrome de lynch ; a propos d'une famille." Amiens, 1988. http://www.theses.fr/1988AMIEM139.
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Takagishi, Yoshiko, 芳子 高岸, and Yoshiharu Murata. "Myosin Va mutation in rats is an animal model for the human hereditary neurological disease, Griscelli syndrome type 1." New York Academy of Sciences, 2006. http://hdl.handle.net/2237/10947.
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Cragun, Deborah Le. "Universal Tumor Screening for Lynch Syndrome: Identification of system-level implementation factors influencing patient reach." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4658.
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Lynch syndrome (LS) is the most prevalent cause of hereditary colorectal cancer (CRC) and confers high risks for several other types of cancer. Universal tumor screening (UTS) of all newly diagnosed patients with CRC can improve LS identification and decrease associated morbidity and mortality among patients and family members. However, for UTS to be effective, patients who screen positive must pursue genetic counseling and confirmatory germline testing (i.e., high patient reach). The purposes of this study were to characterize UTS programs, identify barriers and facilitators to implementation, document whether there have been negative outcomes, and determine institutional and implementation conditions that are associated with high and low patient reach.
Using two conceptual frameworks, RE-AIM and Consolidated Framework for Implementation Research, a baseline survey was conducted of 25 representatives from different institutions performing UTS. Descriptive statistics were used to illustrate similarities and differences among programs. A multiple-case study was then conducted by extracting data from surveys and interviews of representatives from 15 different institutions where UTS programs had been operational for over 6 months and where aggregated patient outcome data were available. Qualitative comparative analysis was performed to make systematic cross-case comparisons and identify conditions uniquely associated with high or low patient reach. Data were triangulated to create models explaining how UTS implementation and system-level factors influence patient reach.
Few patient concerns or negative outcomes were reported. UTS procedures and patient reach were highly variable. All 5 high-reach (H-R) centers have genetics professionals disclose positive screening results and either do not require a referral from another health care provider or have streamlined the referral process. Although 2 of the 5 mid-reach (M-R) centers also share these conditions, they have a less automated follow-up procedure and report difficulty contacting patients as a barrier. Both of the academic institutions with low patient reach (L-R) did not receive patient information that would allow them to follow-up on positive screening results. The three non-academic L-R institutions reported a high proportion of challenges to facilitators during implementation and did not have genetic professionals disclose positive screening results to patients.
Implementing a combination of procedures to streamline UTS protocols and procedures, eliminate barriers to patient follow-through after a positive tumor screen, and incorporate a high level of involvement of genetic professionals in contacting patients and disclosing screening results are expected to lead to improvement in patient reach
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Finnsson, Johannes. "Radiological studies of LMNB1-related autosomal dominant leukodystrophy and Marinesco-Sjögren syndrome." Doctoral thesis, Uppsala universitet, Radiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-303171.
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There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.
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Khoury, Rasha. "Localized biliary ischemia in patients with hepatic arteriovenous malformations, a newly recognized syndrome occurring in hereditary hemorrhagic telangiectasia diagnosis and management." [New Haven, Conn. : s.n.], 2008. http://ymtdl.med.yale.edu/theses/available/etd-12082008-095643/.
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Gaifulina, Riana. "A study of Raman spectroscopy as a clinical diagnostic tool for the detection of lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10024847/.
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Lynch syndrome also known as hereditary non-polyposis colorectal cancer (HNPCC) is a highly penetrant hereditary form of colorectal cancer that accounts for approximately 3% of all cases. It is caused by mutations in DNA mismatch repair resulting in accelerated adenoma to carcinoma progression. The current clinical guidelines used to identify Lynch Syndrome (LS) are known to be too stringent resulting in overall underdiagnoses. Raman spectroscopy is a powerful analytical tool used to probe the molecular vibrations of a sample to provide a unique chemical fingerprint. The potential of using Raman as a diagnostic tool for discriminating LS from sporadic adenocarcinoma is explored within this thesis. A number of experimental parameters were initially optimized for use with formalin fixed paraffin embedded colonic tissue (FFPE). This has resulted in the development of a novel cost-effective backing substrate shown to be superior to the conventionally used calcium fluoride (CaF2). This substrate is a form of silanized super mirror stainless steel that was found to have a much lower Raman background, enhanced Raman signal and complete paraffin removal from FFPE tissues. Performance of the novel substrate was compared against CaF2 by acquiring large high resolution Raman maps from FFPE rat and human colonic tissue. All of the major histological features were discerned from steel mounted tissue with the benefit of clear lipid signals without paraffin obstruction. Biochemical signals were comparable to those obtained on CaF2 with no detectable irregularities. By using principal component analysis to reduce the dimensionality of the dataset it was then possible to use linear discriminant analysis to build a classification model for the discrimination of normal colonic tissue (n=10) from two pathological groups: LS (n=10) and sporadic adenocarcinoma (n=10). Using leaveone-map-out cross-validation of the model classifier has shown that LS was predicted with a sensitivity of 63% and a specificity of 89% - values that are competitive with classification techniques applied routinely in clinical practice.
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Almeida, Gonçalves Sara de. "Identification of new genes involved in hereditary steroid-resistant nephrotic syndrome using next generation sequencing and in vivo functional characterization in drosophila melanogaster." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB030/document.
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Pas de résuméNephrotic syndrome (NS) is a kidney disease characterized by disruption of the glomerular filtration barrier and the massive loss of proteins into the urine. Although in the majority of cases treatment with steroids leads to remission of the disease, in 15-20% of cases the disease is not responsive to this therapy and is classified as steroid-resistant nephrotic syndrome (SRNS). SRNS is a clinical condition with high morbidity leading to progressive renal failure as well as multiple metabolic and cardiovascular complications. Extensive research over the last 20 years has identified more than 40 SRNS causing genes that are crucial for function of the podocyte, a highly specialized kidney epithelial cell. However, the mutated gene is still unknown in about half of the familial cases. We have used exome sequencing to identify new genes mutated in SRNS. In order to prove the pathogenicity of the identified mutations we used the Drosophila model, assessing defects of fly viability and the structure and function of nephrocytes, podocyte like-cells. My thesis work consists of two projects. Firstly, we identified biallelic mutations in a new candidate gene, SGPL1, encoding the sphingosine 1- phosphate lyase, in individuals presenting SRNS with facultative adrenal insufficiency, ichthyosis, neurological defects and immunodeficiency. SGPL1 is the main catabolic enzyme of sphingolipids, irreversibly degrading sphingosine 1-phosphate into phosphoethanolamine and hexadecenal. In flies, these mutations were shown to decrease viability, induce nephrocyte defects and lead to the accumulation of sphingoid bases due to the loss of SGPL1 catabolic activity. Together, these results indicate that the identified SGPL1 mutations are pathogenic and cause a new syndromic form of SRNS. Moreover, in a second project, we defined the contribution of homozygous mutations found in two different genes, ADD3 and KAT2B, to a complex phenotype found in affected individuals from one consanguineous family. These individuals presented with neurological defects, cataracts, mild skeletal defects, cardiomyopathy and SRNS. ADD3 encodes adduciny, an F-actin capping protein that also links the actin cytoskeleton to the spectrin based membrane skeleton, while KAT2B encodes the lysine acetyltransferase 2B, mainly known for acetylation of histones and modulation of transcriptional programs. We found additional nonrelated patients carrying only biallelic ADD3 mutations that presented a partially overlapping syndrome but with no cardiac or renal manifestations. In the Drosophila model we found that both ADD3 and KAT2B mutations impaired fly viability and that the ADD3 mutation also impaired fly motor function. However, only the KAT2B mutation induced functional defects in Drosophila heart and nephrocytes. Altogether, these results suggest that ADD3 mutations are responsible for a neurological phenotype with facultative cataracts and skeletal defects while the KAT2B mutation induces heart and kidney defects. These results highlight the Drosophila as a good in vivo model to test the pathogenicity of the mutations found in SRNS candidate genes
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Whitehead, Caragh (Caragh Bryony). "Molecular analysis of GJB2 (connexin 26) and GJB6 (connexin 30) gene mutations in non-syndromic hereditary deafness in South Africa." Thesis, Stellenbosch : Stellenbosch University, 2004. http://hdl.handle.net/10019.1/50028.
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Thesis (MSc)--University of Stellenbosch, 2004.ENGLISH ABSTRACT: The most common inherited sensory disorder that affects I in 1 000 children is severe hearing loss. In developed countries, about a third of cases have a genetic origin, 80% of which are autosomal recessive forms (DFNB). Before 1993 few genes causing hearing loss had been identified, but since then a large number of genes related to this problem have been identified. Studies indicate that the DFNBI locus, located at position 13q11-12, contributes to 20% of all childhood deafness and may have a carrier rate as high as 2.8%. There are two genes linked to DFNB 1, GJB2 and GJB6, which are the major genetic cause of non-syndromic autosomal recessive deafness. GJB2 and GJB6 encode the connexin proteins connexin 26 and 30 (Cx26 and Cx30), respectively. The specific aim of this study was to determine the role of GJB2 and GJB6 in deafness within the South African population, since there are no published results involving South African patients with non-syndromic autosomal recessive deafness. This study therefore involved the identification of mutations within the coding region of the GJB2 and GJB6 genes in the South African population and the determination of their specific allele frequencies. Another aim of this study was to analyse the effectiveness of three single-strand conformation polymorphic (SSCP) gel electrophoresis systems in the detection of GJB2 mutations, for use in a standardised diagnostic program. A total of 44 families were recruited and divided into either the familial or sporadic study group, which consisted of 16 and 28 families, respectively. Control samples were also screened from 50 Caucasians and 50 Mixed Ancestry individuals collected from the general population. To achieve the aims of this study, polymerase chain reaction (PCR) amplification followed by automated DNA sequencing of the coding regions of GJB2 and GJB6 was performed. The three SSCP systems that were tested for their effectiveness in detecting mutations within the coding region of GJB2 included mini polyacrylamide, SSCP-urea and two buffer gel electrophoresis systems. In total, six previously reported mutations (35delG, 312de1l4, W24X, M34T, V37I and W44X), a novel mutation (N62I), and four benign polymorphisms (V27I, A40A, R127H and V153I) were detected in GJB2. In the GJB6 gene only the S199T polymorphism was observed. It was determined that the most common mutations found within the Caucasian and Mixed Ancestry populations of South Africa were 35delG and 312de1l4 of GJB2. An overall detection rate of 35.227% was achieved in non-syndromic autosomal recessive deafness amongst this patient cohort. It was also observed that none of the SSCP gel electrophoresis systems were effective at detecting all of the GJB2 mutations. This could change if the systems were specifically optimised for the cornmon mutations that were identified. This study therefore, provides information that can be used in the formulation of a screenmg program for non-syndromic autosomal recessive deafness specific to the South African population. Further research should be conducted involving other genes, in addition other population groups of South Africa to provide a more comprehensive genetic diagnostic and counselling tool.
AFRIKAANSE OPSOMMING: Die mees algemene oorerflike sensoriese steuring wat 1 in 1 000 kinders affekteer is ernstige gehoorverlies. In ontwikkelde lande het omtrent een-derde van die gevalle 'n genetiese oorsprong, waarvan 80% outosomaal resessiewe vorms is (DFNB). Tot en met 1993 is min gene wat gehoorverlies veroorsaak geïdentifiseer, maar sedertdien is 'n groot aantal gene gelokaliseer en verskeie is ook al gekloneer. Studies toon dat die DFNB 1 loci, wat in posisie 13q 11-12 gevind word, 20% van doofheid in kinders veroorsaak, en dit het 'n draer frekwensie van so hoog as 2.8%. Twee gene wat koppeling met DFNBI toon, GJB2 en GJB6, is die vernaamste genetiese oorsaak van nie-sindromise autosomaal resessiewe doofheid. GJB2 en GJB6 koder vir die connexin proteïne 26 en 30 (Cx26 en Cx30), onderskeidelik. Die spesifieke doel van hierdie studie is om die rol van GJR2 en GJB6 in doofheid binne die Suid- Afrikaanse populasie te bepaal, aangesien daar tans nog geen gepubliseerde resultate omtrent Suid- Afrikaanse pasiënte met nie-sindromiese outosomaal resessiewe doofheid is nie. Hierdie studie handel dus oor die identifikasie van mutasies wat binne die koderende areas van die GJR2 en GJB6 gene voorkom in die Suid-Afrikaanse populasie, asook oor die bepaling van hulle spesifieke alleel frekwensies. Verder het hierdie studie ten doelom die effektiwiteit van drie enkel-string konformasie polimorfisme (SSCP) gel-elektroforese metodes in die opsporing van GJB2 mutasies te analiseer met die oog op toekomstige gebruik in 'n gestandardiseerde diagnostiese program. Altesaam 44 families is ingesamel en gekategoriseer in familiële of sporadiese studie-groepe met 16 en 28 families onderskeidelik. Kontrole monsters van 50 Kaukasiese en 50 Gemengde Herkoms individule uit die algemene populasie is ook getoets. Om die doeleindes van die studie te bereik is PKR amplifikasie en outomatiese DNS volgordebepaling van die koderende area van GJB2 en GJR6 gedoen. Die drie SSCP sisteme wat getoets is vir hulle effektiwiteit in die identifisering van mutasies in die koderende area van GJB2 sluit in mini poli-akrielamied, urea en twee-buffer gel elektroforese sisteme. In totaal is ses gerapporteerde mutasies (35delG, 312de114, W24X, M34T, V37I en W44X), 'n nuwe mutasie (N62I), en vier onskadelike polimorfismes (V27I, A40A, R127H en V153I) opgespoor in GJB2, maar in GJB6 is net die S199T polimorfisme waargeneem. Uit die resultate kon afgelei word dat 35deiG en 312de114 van GJB2 die mees algemene mutasies binne die Kaukasiese en Gemengde Herkoms bevolkings van Suid Afrika is. Die total ontdekking standaard van 35.227%· vir nie-sindromise autosomaal resessiewe doofheid tussen herdie patient kohort was bereik. Verder is waargeneem dat geen van die SSCP gel elektroforese metodes effektief was om al die mutasies van GJB2 op te spoor nie. Die situasie kan egter verander as die sisteme spesifiek geoptimiseer word vir die algemene mutasies wat gevind is. Hierdie studie verskaf dus inligting wat gebruik kan word in die verskaffing van 'n diagnostise program vir nie-sindromise outosomaal resessiewe doofheid wat spesifiek is vir die Suid- Afrikaanse populasie. Verdere navorsing wat ander gene en ander populasie groepe van Suid-Afrika insluit, behoort egter uitgevoer te word om uiteindelik 'n meer uitgebreide genetiese diagnostiese en raadgewing diens daar te stel.
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Araujo, Monica Rodrigues. "Perspectives and Experiences of Individuals Undergoing Predictive Testing for Hereditary Breast and Ovarian Cancer (HBOC) Syndrome in the Western Cape, South Africa." Master's thesis, Faculty of Health Sciences, 2018. http://hdl.handle.net/11427/30057.
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Breast cancer is the most common malignancy affecting females globally. Hereditary breast and ovarian cancer (HBOC) syndrome is caused by pathogenic variants in BRCA1 and BRCA2 and is seen in approximately 50% of families with a strong history of breast and ovarian cancers. Predictive testing (PT) is offered to unaffected individuals with a positive family history of HBOC, with an already identified BRCA1 or BRCA2 mutation in an affected family member. There is an overwhelming amount of research that has focused on the after-effects of diagnostic genetic testing for HBOC but there has been little investigation into how individuals experience the actual PT process. The present study therefore aimed to investigate individuals’ decisions for undergoing and their experiences of PT for HBOC in a local context, by focusing on at-risk South African individuals residing in the Western Cape Province. Sixteen participants were recruited retrospectively from the breast cancer and/or clinical genetics clinics at Groote Schuur Hospital, Tygerberg Hospital and private genetic counselling practices in Cape Town. Semi structured interviews were conducted, and the interview transcripts were analysed using the framework approach for qualitative data analysis. Using this approach, five themes were identified relating to the perspectives and experiences of individuals undergoing PT for HBOC, in selected settings in the Western Cape. While some participants felt that their decision to pursue PT was influenced by their family history of cancer and the associated cancer-related distress, others felt that their decision was made out of a sense of duty to their families or in solidarity with those that were affected or received a positive test result. Overall, the participants felt that the pre-test counselling was beneficial in allowing for an improved understanding of HBOC, however not all participants felt that the pre-test counselling prepared them for receiving their results. Receiving a negative test result was often accompanied by feelings of guilt and did not exempt participants from the fear of developing cancer. Some of the concerns raised by participants that received a positive test result were centred around prophylactic intervention and its effect on body image. Overall, participants felt empowered by their mutation status and felt that they were better able to manage their risk. The need for additional support, both practical and emotional support, was particularly evident amongst mutation-carriers. The findings of this study provide valuable insight into the perspectives and experiences of this population, which could potentially impact the services that are provided to individuals undergoing PT for HBOC in similar settings.
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Vanderwal, April. "Factors that Influence the Management Recommendations Breast Surgeons Provide to Women with Pathogenic Variants in Moderate Penetrance Breast Cancer Susceptibility Genes." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592133660069865.
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Lu, Simin. "Calcium Dependent Regulatory Mechanism in Wolfram Syndrome: A Dissertation." eScholarship@UMMS, 2002. http://escholarship.umassmed.edu/gsbs_diss/733.
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Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration. Two causative genes have been identified so far, WFS1 and WFS2, both encoding endoplasmic reticulum (ER) localized transmembrane proteins. Since WFS1 is involved in the ER stress pathway, Wolfram syndrome is considered an ER disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome, the molecular mechanism linking ER to the death of β cells and neurons has not been elucidated.
The endoplasmic reticulum (ER) is an organelle that forms a network of enclosed sacs and tubes that connect the nuclear membrane and other organelles including Golgi and mitochondria. ER plays critical functions in protein folding, protein transport, lipid metabolism, and calcium regulation. Dysregulation of ER function disrupts normal cell metabolism and activates an array of anti-survival pathways, eventually leading to disease state.
Here we show that calpain is involved in both prototypes of Wolfram syndrome. Calpain 2 activity is negatively regulated by WFS2 protein, and hyper-activation of calpain 2 by WFS2-knockdown leads to cell death. Calpain hyper-activation is also present in WFS1 loss of function cells due to the high cytosolic calcium. Extensive calpain activation exists in the Wolfram syndrome mouse model as well as in patient cells. A compound screen targeting ER homeostasis reveals that dantrolene, a ryanodine receptor inhibitor, can prevent cell death in cell models of Wolfram syndrome. Our results demonstrate that the pathway leading to calpain activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.
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Lu, Simin. "Calcium Dependent Regulatory Mechanism in Wolfram Syndrome: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/733.
Full textAbstract:
Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration. Two causative genes have been identified so far, WFS1 and WFS2, both encoding endoplasmic reticulum (ER) localized transmembrane proteins. Since WFS1 is involved in the ER stress pathway, Wolfram syndrome is considered an ER disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome, the molecular mechanism linking ER to the death of β cells and neurons has not been elucidated.
The endoplasmic reticulum (ER) is an organelle that forms a network of enclosed sacs and tubes that connect the nuclear membrane and other organelles including Golgi and mitochondria. ER plays critical functions in protein folding, protein transport, lipid metabolism, and calcium regulation. Dysregulation of ER function disrupts normal cell metabolism and activates an array of anti-survival pathways, eventually leading to disease state.
Here we show that calpain is involved in both prototypes of Wolfram syndrome. Calpain 2 activity is negatively regulated by WFS2 protein, and hyper-activation of calpain 2 by WFS2-knockdown leads to cell death. Calpain hyper-activation is also present in WFS1 loss of function cells due to the high cytosolic calcium. Extensive calpain activation exists in the Wolfram syndrome mouse model as well as in patient cells. A compound screen targeting ER homeostasis reveals that dantrolene, a ryanodine receptor inhibitor, can prevent cell death in cell models of Wolfram syndrome. Our results demonstrate that the pathway leading to calpain activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.
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Alaa, El Din Ferdos. "Le syndrome de Rendu-Osler-Weber : aspects génétiques, moléculaires et épidémiologiques." Thesis, Poitiers, 2015. http://www.theses.fr/2015POIT2260/document.
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La télangiectasie hémorragique héréditaire (HHT) est une maladie rare (1/10.000). Son incidence est plus élevée (pouvant atteindre 1/1000) dans certaines zones géographiques dont la région Poitou-Charentes. Cette maladie autosomique dominante est causée par des mutations d'un des trois gènes identifiés ENG, ACVRL1 et SMAD4 codant pour des protéines de la voie BMP spécifiquement exprimés dans les cellules endothéliales. Le nombre croissant de mutations détectées chez les patients et l'expressivité variable de certaines mutations nous a ammené à déterminer les conséquences de mutations afin d'établir une corrélation génotype/phénotype. Cette corrélation est importante pour le conseil génétique et évidemment le diagnostic prénatal. Dans ce contexte, nous avons étudié aux niveaux cellulaire et moléculaire les effets de plusieurs mutations. L'effet délétère de ces mutations sur la protéine et/ou l'épissage de l'ARN a été évalué. Nous avons montré que sur les 23 mutations d'ACVRL1 : 1) 18 mutations faux-sens affectent la fonctionnalité de la protéine en réponse à BMP9 et 3 mutations sont de simples polymorphismes, 2) la mutation exonique c.733A>G (p.Ile245Val) affecte l'épissage de l'exon 6, 3) La mutation c.1048+5G>A de l'intron 7 en dehors du site consensus induit un épissage aberrant de l'exon 7. En ce qui concerne l'ENG, nous avons analysé 4 mutations et nous avons montré que la mutation c.1088G>A (p.Cys363Tyr) a un impact sur l'activité du récepteur et que les mutations c.1134G>A (p.Ala378Ala) et c.1060C>T (p.Leu364Leu) altèrent l'épissage de l'exon 8. Ce travail montre l'importance de l'étude approfondie de toute nouvelle mutation par des études in silico, in vitro et in cellulo à différents niveaux cellulaires. Des études in vivo ultérieures peuvent compléter et appuyer la stratégie expérimentale que nous avons suivieHereditary hemorrhagic telangiectasia (HHT) is a rare disease (1/10.000). Its incidence is higher in certain geographic areas including the Poitou-Charentes region (1/1000). This autosomal dominant disease is caused by mutations in one of three identified genes ENG, ACVRL1 and SMAD4 encoding BMP pathway proteins specially expressed in endothelial cells. The increasing number of mutations detected in patients and the variable expressivity of certain mutations has taken us to determine the consequences of mutations to establish a genotype/phenotype correlation. This correlation is important for genetic counseling and obviously for prenatal diagnosis. In this context, we investigated the effects of several mutations at the cellular and molecular levels. The deleterious impact of these mutations on the protein and/or RNA splicing was evaluated. We have shown that for the 23 mutations of ACVRL1: 1) 18 missense mutations affect the functionality of the protein in response to BMP9 and 3 are polymorphisms, 2) exonic mutation c.733A>G (p. Ile245Val) affects the splicing of the exon 6, 3) mutation c.1048+5G>A in intron 7 off the consensus site induces an aberrant splicing of exon 7. Concerning the ENG, we analyzed 4 mutations and we showed that the mutation c.1088G> A (p.Cys363Tyr) has an impact on the activity of the receptor and that the mutations c.1134G> A (p.Ala378Ala) and c.1060C> T (p.Leu364Leu) inhibit the splicing of exon 8. This work shows the importance of the comprehensive study of any new mutation by in silico, in vitro and in cellulo studies at different cellular levels. The in vivo studies can further complement and support the experimental strategy that we followed
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Chiang, Jen-Chieh. "Dosage Compensation of Trisomy 21 and Its Implications for Hematopoietic Pathogenesis in Down Syndrome." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/931.
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Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis.
By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels.
Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients.
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Chiang, Jen-Chieh. "Dosage Compensation of Trisomy 21 and Its Implications for Hematopoietic Pathogenesis in Down Syndrome." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/931.
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Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis.
By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels.
Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients.
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Xiao, Xue. "Investigation of the impact of HNPCC gene deficiency on outcome in epithelial ovarian cancer." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/19546.
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Hereditary non-polyposis colon cancer syndrome (HNPCC) is associated with an increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. HNPCC results from a germline mutation in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, PMS1, PMS2, MSH6, MSH3 and MLH3. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. The goal of this project was to study MMR deficiency in ovarian cancer at both the clinical and molecular level. The first aim was to examine the frequency of MMR loss in a large patient cohort and investigate the clinical consequences of MMR deficiency. The second aim was to describe the molecular characteristics of MMR deficiency in ovarian cancer cell lines and establish an in vitro cell line model of MMR deficiency in ovarian cancer. The third aim was to identify synthetic lethal strategies for the treatment of ovarian cancer to maximise cytotoxicity in a MMR-deficient background. In order to characterise the clinical consequences of MMR deficiency, a large patient cohort was studied with regard to MMR status. Three tissue microarrays consisting of 581 ovarian tumours were constructed, and expression of the four most frequently lost MMR proteins: MLH1, MSH2, PMS2 and MSH6 were detected by immunohistochemistry. Afterwards, MMR status and histology subtypes were analysed in combination with the associated clinical data. The overall incidence of MMR deficiency (loss of any MMR protein) was 15.7%, with PMS2 being the most frequently lost protein (9.7%). In addition, MMR deficiency tended to appear in a grouped fashion: MLH1 with PMS2; MSH2 with MSH6. Patients with non-serous subtypes of ovarian cancer, clear cell or mucinous especially, had higher incidence of MMR deficiency compared to patients with serous ovarian cancer. Overall MMR deficient patients were more likely to be diagnosed at early stages compared with MMR proficient patients, and this is probably due to the association between MMR deficiency and non-serous histology. However, platinum-based treatment for patients with MMR deficiency gives no advantage over those without MMR deficiency. Therefore better treatments for this subgroup of patients may be needed. The features of MMR deficiency in ovarian cancer were also characterized at the molecular level. After quantifying mRNA and protein expression of MMR genes in 19 ovarian cell lines, three cell lines (SKOV3, TOV21G and IGROV1) were found to have a defect in MLH1 expression at both the mRNA and protein level. Interestingly, the three cell lines also carried a defect in PMS2 expression at the protein level but not at the mRNA level, which is consistent with our clinical data demonstrating that MLH1 protein and PMS2 protein are paired in loss. In addition, across the 19 cell lines, MLH1 and PMS2 showed positive correlation at both the mRNA level (R=0.53, p=0.02) and protein level (R=0.72, p=0.0006). In order to study co-expression of MLH1 and PMS2, a plasmid encoding the cDNA for MLH1 was transfected into the three MLH1 deficient cell lines; and conversely siRNA targeting MLH1 was transfected into the MMR proficient cell line A2780 and expression of MLH1 protein and PMS2 protein was quantified. The results showed that re-introduction of MLH1 into MLH1 deficient cells resulted in increased expression of PMS2 protein, while knocking down MLH1 in MMR proficient cells leads to decreased PMS2 protein expression. This indicates that MLH1 may play a crucial role in regulating PMS2 protein expression. As the three MLH1 and PMS2 protein deficient cell lines all express PMS2 mRNA, the regulation of PMS2 expression by MLH1 is likely to be at the translational or post-translational level. However, the expression of PMS2 protein was not increased in the absence of MLH1, even when the proteasomal and lysosomal protein degradation pathways were blocked (as seen with SKOV3 cells), suggesting decreased PMS2 protein expression is not due to rapid degradation in the absence of MLH1. Therefore MLH1 may play a role in regulating the synthesis of PMS2 protein at the translational level, rather than preventing the degradation of PMS2. Thus, to investigate the mechanism by which PMS2 protein levels are regulated by MLH1, future work should focus on translational regulation of PMS2. In order to identify synthetic lethal strategies to target MMR deficiency in ovarian cancer, an isogenic cell line model of MMR deficiency was established by stable transfection of a plasmid for MLH1 and its corresponding empty vector into SKOV3 cells. The MLH1+ cell line SAC-1 and MLH1- cell line SN-5 were selected for drug screening based on their phenotype and growth rate. The AlamarBlue assay, with z’ above 0.5, was chosen for drug screening and a kinase inhibitor library containing 362 drugs of known target was screened. Two drugs with similar structures that targeted PLK1 showed greater growth inhibition of SN-5 compared with SAC-1. When the two cell lines were treated with another PLK1 inhibitor, BI2536, with different structure, a 2-fold difference in growth inhibition between SAC-1 and SN-5 was also observed, suggesting PLK1 is a potential synthetic lethal target for MLH1 deficiency in ovarian cancer. Together these data demonstrate that clinically, MMR deficiency is associated with non-serous subtypes of ovarian cancer and specific MMR proteins are paired in loss. While current standard therapy offers no selective benefit to ovarian cancer patients with MMR deficiency, inhibiting PLK1 activity may confer selective benefit.
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Popinet, Sylvestre. "Dysplasie fibreuse des os et syndrome de Mac Cune Albright : une nouvelle physiopathologie, revue de la littérature à propos d'un cas." Bordeaux 2, 1997. http://www.theses.fr/1997BOR23083.
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Uehara, Daniela Tiaki. "Pesquisa de microrrearranjos em genes candidatos a surdez sindrômica e não-sindrômica." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-22022011-111240/.
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A complexidade da fisiologia da audição resulta da participação e interação de produtos de grande número de genes, razão pela qual a surdez hereditária exibe enorme heterogeneidade genética. Estudos moleculares nas duas últimas décadas permitiram a identificação de vários genes responsáveis por surdez; entretanto, muitos ainda restam ser identificados. A maioria dos estudos de mapeamento de genes de surdez até então conduzidos privilegiou estratégias que buscavam mutações de ponto. Outros mecanismos mutacionais, como deleções e duplicações, foram pouco investigados. Portanto, a contribuição das CNVs (Copy Number Variations) na surdez hereditária é pouco conhecida. O objetivo desse trabalho foi identificar novos genes que possam ter papel na etiologia da surdez sindrômica ou não-sindrômica por meio da investigação de microdeleções e microduplicações em pacientes com perda auditiva. Selecionamos 25 genes candidatos (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 e TUBB2A) para a triagem de microrrearranjos por meio da técnica de MLPA (Multiplex Ligation-dependent Probe Amplification). Os genes candidatos foram selecionados a partir de rearranjos detectados em um estudo prévio realizado por meio de array-CGH (array-based Comparative Genomic Hybridization) em indivíduos com surdez sindrômica estudados em nosso laboratório, e também a partir de dados da literatura. Nossa casuística foi composta por 163 indivíduos, dos quais 74 são pacientes com surdez associada a outros sinais (sindrômicos), a maioria casos isolados, e 89 são pacientes com surdez não-sindrômica, propósitos de famílias em que segrega surdez de herança autossômica dominante ou recessiva. Desenhamos uma sonda sintética intragênica de MLPA para cada um dos genes candidatos. Foram detectadas seis deleções em TMC6 (3,7%), seis deleções e uma duplicação em STRC (4,3%) e uma duplicação em IMMP2L (0,6%). A triagem de alterações nesses três genes em 189 indivíduos fenotipicamente normais revelou quatro deleções em TMC6 (2,1%), oito deleções e três duplicações em STRC (5,8%) e três deleções em IMMP2L (1,6%). Todas as alterações em TMC6, tanto nos casos de surdez como nos controles, eram na realidade artefatos devidos a problemas de hibridação da sonda correspondente. No gene STRC, previamente já relacionado à surdez, os rearranjos nos indivíduos afetados devem se tratar de polimorfismos sem efeito fenotípico por serem muito frequentes na população. Contudo, é possível que haja nesses pacientes mutações adicionais que não puderam ser rastreadas e que poderiam contribuir ao fenótipo, em combinação com o rearranjo detectado, como já descrito em um caso da literatura. A duplicação em IMMP2L em uma paciente com surdez não-sindrômica, herdada da mãe igualmente afetada, mostrou-se a mais provavelmente relacionada ao fenótipo, pois o estudo complementar por meio de array-CGH revelou que o rearranjo inclui uma duplicação parcial da porção 3 de outro gene, DOCK4. O produto desse gene possui uma isoforma que se localiza nos estereocílios das células ciliadas e se liga a uma importante proteína relacionada à audição, a harmonina. Portanto, nossa hipótese é a de que a duplicação seja a causa da surdez na família e que DOCK4 seja um novo gene responsável por surdez. A associação de IMMP2L com surdez é menos provável devido ao grande número de CNVs não patogênicas já descritas que incluem partes desse gene. Estudos complementares são necessários para mapear a duplicação com mais precisão. Além disso, o rastreamento de mutações em DOCK4 em outras famílias com surdez pode vir a confirmar o possível papel desse gene na etiologia da surdez.Several genes contribute to the complexity of physiology of hearing. Consequently, hereditary deafness is extremely heterogeneous from the genetic point of view. In the last two decades, several genes responsible for hereditary hearing loss have been identified, but a large number of genes remains to be found, as evidenced by the unexplained cases of inherited deafness. The search for point mutations in candidate genes after mapping based on linkage studies has been the main strategy in the identification of such genes. Other mutation mechanisms, such as deletions and duplications, have been rarely investigated, and the contribution of DNA copy number variants (CNVs) to hearing loss is not well known. This study aimed at identifying novel genes, which might play a role in the etiology of syndromic and non-syndromic deafness, through the search of gene microdeletions and microduplications. We selected 25 candidate genes (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 and TUBB2A) based on their involvement in microimbalances detected by Array-based Comparative Genomic Hybridization (aCGH) in a previous study of a Brazilian sample of individuals with syndromic hearing loss from our laboratory and others reported in the literature. We studied 163 subjects, 74 of them presenting syndromic deafness, the majority were isolated cases, and 89 being probands of families in which nonsyndromic deafness had an autosomal dominant or recessive mode of inheritance. Gene deletions or duplications were screened by Multiplex Ligant-dependent Probe Amplification (MLPA) using one synthetic intragenic probe designed for each candidate gene. We detected six deletions in TMC6 (3,7%), six deletions and one duplication in STRC (4,3%), and one duplication in IMMP2L (0,6%). The screening of imbalances in these genes in a control sample of 189 hearing individuals revealed four deletions in TMC6 (2,1%), eight deletions and three duplications in STRC (5,8%) and three deletions in IMMP2L (1,6%). The imbalances found in TMC6, both in affected and control individuals, were in fact artifacts due to problems in the hybridization of the corresponding probe. As to the STRC gene, previously related to deafness, the imbalances are more likely to be 4 polymorphisms with no phenotypic effect. However, the possibility remains that additional undetected mutations in affected individuals contribute to their phenotype, in combination with the microrearrangement, as already reported in the literature. The duplication in IMMP2L in a non-syndromic patient, and also present in her affected mother, is most likely causative of deafness, since a complementary study performed with aCGH revealed that the rearrangement included a partial duplication of the 3 end of another gene, DOCK4. An isoform of the DOCK4 protein localizes to the stereocilia in the inner ear and interacts with harmonin, a protein already known to be involved in hearing. We hypothesize that this duplication may be the cause of deafness in the family and, this being the case, DOCK4 appears as a novel deafness gene. The causal association between IMMP2L and deafness is less plausible, because of the large number of reported non-pathogenic CNVs that include parts of this gene. Further studies are required to precisely map this duplication. In addition, the screening of mutations in DOCK4 in other families with hearing impairment is required to evaluate its possible role in the etiology of deafness.
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Arveiler, Benoît. "Biologie moleculaire de maladies liees au chromosome x : localisation des genes responsables de trois immunodeficiences et de deux formes de retard mental non specifique, cartographie genetique et physique de la region xq26-q28 contenant le locus de l'x fragile." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13191.
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