Academic literature on the topic 'Eye Diseases, Hereditary – genetics'

Eye disease is an increasing problem, exacerbated by ageing populations in most countries. The National Eye Institute in the USA predicts that the cases of age-related macular degeneration (AMD) and glaucoma around the world will double by 2050. According to the World Health Organisation, these two diseases account for six per cent of all cases of visual impairment and blindness globally. Visual impairment affects quality of life and productivity and is therefore an important area of research. Professor Takeshi Iwata's laboratory is making ground-breaking discoveries in the specialist area of genetically-influenced retinal diseases. Most eye diseases are partly due to genetics, but the influence of a person's genotype is more profound in hereditary diseases such as retinitis pigmentosa and macular dystrophy. Specific genotypes are less influential, but play a role in AMD and glaucoma. The Iwata laboratory investigates AMD, glaucoma and 36 hereditary retinal diseases, to determine the genetic mutations that cause or predispose a patient towards developing disease. Iwata says: 'Our goal is to develop therapies for retinal eye diseases based on fundamental research into their molecular mechanisms.' Determining the genetic mutations behind each disease is the first step to realising this goal. As many of the hereditary retinal diseases are rare, collaboration is very important to the laboratory's work. To collect samples from a large number of patients, Iwata explains: 'We founded the Japan Eye Genetics Consortium (JEGC), a group comprising 30 ophthalmology departments throughout Japan.' Clinicians enter patients' phenotype information into a national genotype-phenotype database and send saliva or blood samples to the Iwata laboratory for gene analysis. Iwata explains: 'Following analysis, we upload whole exome and genome analysis results to the database to share amongst the collaborators.' The JEGC is already yielding important results. 80 per cent of families studied were found to have previously unidentified mutations. Functional analysis is underway to characterise each of these gene mutations in detail. Over 1366 family pedigrees have been collected, and the consortium aims to gather 5000 in total. In 2014, a more ambitious consortium was launched. The aim of the Asian Eye Genetics Consortium (AEGC), Iwata explains, is: 'to identify all the gene mutations responsible for hereditary eye diseases in the Asian population.' Over 150 scientists from 20 countries have been brought together through the consortium.

Deciphering the relative roles of heredity and environmental factors ("nature vs. nurture") in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and putative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. In addition, during the 30-year period between 1958 and 1987, only meager resources were targeted toward the "nature" side of the nature/nurture dipole in periodontology. In this article, we present a brief history of the development of genetic epistemology, then describe the three main research mechanisms by which questions about the hereditary component of diseases in humans can be addressed. A critical discussion of the evidence for a hereditary component in caries susceptibility is next presented, also from a historical perspective. The evolution of knowledge concerning possible genetic ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory periodontal disease is initiated with an analysis of some foreign-language (primarily German) literature that is likely to be unfamiliar to the reader. We identify a turning point at about 1960, when the periodontal research community turned away from genetics in favor of microbiology research. During the past five years, investigators have re-initiated the search for the hereditary component in susceptibility to common adult periodontal disease; this small but growing body of literature is reviewed. Recent applications of in vitro methods for genetic analyses in periodontal research are presented, with an eye toward a future in which persons who are at risk-genetically predisposed-to periodontal disease may be identified and targeted for interventive strategies. Critical is the realization that genes and environment do not act independently of each other; the appearance or magnitude of heritability may differ with various environments.

What do opioids have to do with ophthalmology? With recent developments in DNA research and gene modification, perhaps more than you might imagine. Naturally occurring opioids have been found in the DNA of certain milk cows, and it appears possible that the type of gene mutation that produces the opioid effect in milk and meat may also produce genetic abnormalities in the human genome, leading to hereditary ophthalmic syndromes, and diseases such as autism, Alzheimer’s disease, heart disease and other chronic diseases. The identification, isolation, and subsequent modification of these genes would appear to be a step toward the eradication of the diseases associated with them.

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

Исследования наследственной патологии органа зрения на фоне широкой генетической гетерогенности и выраженного клинического полиморфизма затруднены по причине сложности определения очага первичного повреждения. Часто заболевания переднего отрезка глаза являются пусковыми для повреждения заднего отрезка (сетчатки, хориоидеи, зрительного нерва). В представленном сообщении описана структура спектра РАХ6-ассоциированной патологии органа зрения в клинически полиморфной выборке с учетом уровня поражения глазного яблока. Studies of hereditary pathology of the eye against the background of broad genetic heterogeneity and pronounced clinical polymorphism are difficult because of the complexity of determining the focus of primary damage - often diseases of the anterior segment of the eye are triggers for damage to the posterior segment (retina, choroid, optic nerve). The presented report describes the structure of the spectrum of PAX6-associated pathology of the eye in a clinically polymorphic sample, taking into account the level of damage to the eyeball.

ABSTRACT Deciphering the relative roles of heredity and environmental factors (“nature vs. nurture”) in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and mutative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. A critical discussion of the evidence for a hereditary component in caries susceptibility is presented, also from a historical perspective. Recent applications of in vitro methods for genetic analyses in periodontal research are also being discussed, with an eye toward a future in which persons who are at risk, i.e., genetically predisposed to periodontal disease may be identified and targeted for interventional strategies. The evidence for the influence of genetics in dental anomalies and malocclusion has also been discussed. The most important conclusion of this review is: while phenotype is inevitably the result of both genetic and environmental factors, there is irrefutable evidence for a significant genetic influence in many genetic and occlusal variables.

The aim of the study is to present the different electrophysiological methods (EF) for study the retinal function and to highlight their importance in the diagnosis of hereditary retinal dystrophies (HRDs). EF methods are objective methods including the different types of electroretinography (ERG) and electrooculography (EOG). They are “the golden standard” in the diagnosis of retinal dystrophies. EF are especially valuable in the initial stages of the diseases and in asymptomatic forms. They are also particularly important for monitoring the changes in dynamics, which is very important for the diseases prognosis. HRDs are a heterogeneous group of diseases with a relatively low frequency in the human population, characterized by involvement of different retinal layers, most often the complex retinal pigment epithelium-photoreceptors and causing severe visual impairment - loss of night vision, visual field, color vision and visual acuity in the initial stages and leading to progressive and severe loss of visual function by altering the retinal anatomy and function. By EF studies can evaluate the function of the retina in patients with these “rare eye diseases”. EF methods are most important in the diagnosis of HRDs. They are also important in the differential diagnosis between the different retinal dystrophies. A major challenge for the ophthalmologists is to identify the diseases in the early stages. There is an urgent need for more knowledge and practical use of these methods for accurate diagnosis which is a prerequisite for a proper therapy.

Abstract In recent years, the knowledge regarding molecular mechanisms of skin, hair and eye colouration in vertebrates has significantly broadened. It was found that some of the identified coat colour genes show negative pleiotropic effect. They are associated with hereditary diseases, often of a lethal character. Most of these diseases have their counterparts in humans. There is no effective treatment for these diseases, therefore animal models can help to identify the genetic background of diseases and to develop appropriate treatment. Much less is known on the association of coat colour with animal performance. However, there are reports on the effect of coat colour on body measurements and milk production in subtropical environments. The knowledge on pleiotropic effects of coat colour genes is important for breeders who should be aware of the consequences of their decision on mating animals with given genotype.

Orientadores: Antonio Sergio Ramalho, Luis Alberto Magna<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas<br>Made available in DSpace on 2018-08-08T02:28:10Z (GMT). No. of bitstreams: 1 Rim_PriscilaHaeHyun_M.pdf: 5489420 bytes, checksum: b193fb510af9e3efd86456897b14ae59 (MD5) Previous issue date: 2006<br>Resumo: O presente trabalho tem por objetivos verificar a percepção de oftalmologistas brasileiros em relação à contribuição da Genética em sua atuação médica rotineira e a conduta frente a portadores de doenças hereditárias; investigar o nível de conhecimento e a conduta desses pacientes a respeito de sua condição e verificar a contribuição do aconselhamento genético na vida destes pacientes. Duzentos oftalmologistas que atuam na região de Campinas, SP, Brasil (universidades e/ou clínicas particulares) foram convidados a participar, por via postal, de uma entrevista sobre os seus conhecimentos, práticas e opiniões no campo da genética. A casuística de pacientes foi constituída por 53 portadores de deficiência visual importante (acuidade visual com a melhor correção menor que 0,3), de provável etiologia genética, entrevistados em um hospital universitário no período de 18 meses. O conteúdo da entrevista consistiu de perguntas sobre seus conhecimentos, opiniões, condutas e a situação ocular relativos à sua condição, utilizando-se de questionários de múltipla escolha, que permitiram a análise estatística, com comparação de proporções e testes de associação. Examinou-se também uma amostra-controle, constituída por 142 irmãos normais de pacientes, para comparação de alguns indicadores de integração social, principalmente o estabelecimento de parcerias conjugais estáveis e reprodução. Dentre os 73 profissionais que responderam o questionário (36%), foram constatadas altas taxas (49% a 88%) de respostas positivas sobre os seus conhecimentos básicos de genética, porém baixas taxas (10% a 33%) de utilização desses conhecimentos na rotina clínica. Apenas 45% dos indivíduos com oftalmopatias hereditárias receberam aconselhamento genético, geralmente fornecido pelo próprio oftalmologista. O encaminhamento a serviço de genética foi observado em 25% dos casos. O aconselhamento genético foi uma das variáveis que, juntamente com o sexo feminino e o maior nível educacional, mostraram-se associadas a mudanças no planejamento familiar. Embora os pacientes tenham revelado maior dificuldade no estabelecimento de vínculos reprodutivos estáveis, eles tiveram filhos na mesma proporção que os seus irmãos sem a deficiência visual, o que reforça a importância do aconselhamento genético. O potencial terapêutico e preventivo do aconselhamento genético não está sendo explorado adequadamente na prevenção da cegueira. A genética merece ser discutida de forma menos teórica e mais pragmática, não somente entre os oftalmologistas, mas entre os médicos e a população em geral, sobre a aplicação do potencial da genética em benefício dos pacientes, por meio de um aconselhamento genético abrangente, direcionado para a comunidade<br>Abstract: This study verified the perception and behavior of Brazilian ophthalmologists in relation to hereditary eye diseases and the contribuition of Genetics in their routine practice; and verified the perception and behavior of patients with severe visual impairment and the contribuition of genetic counseling in their lives. Invitations were posted to 200 ophthalmologists, who practice in the area of Campinas, SP, Brazil, to participate in an interview concerning their knowlegde, behavior and opinions in the field of Genetics. Patients sample was composed of 53 individuals with severe visual impairment (visual acuity of less than 0.3 in the better eye with the best correction) caused by genetic factors. The interviews were held in a university hospital over a period of 18 months. The multiple-choice questionnaire applied permitted statistical analysis, for proportion comparisons and associative tests. A control sample composed of 142 normal patients siblings was also examined to compare some social integration indicators - mainly the establishment of stable couples and reproduction. Of the 73 professionals who answered the questionnaire (36%), the percentage of affirmative responses regarding basic genetic knowledge was high (49% to 88%) but the application of this knowledge to regular clinical routine was poor (10% to 33%). Only 45% of the individuals with hereditary ophthalmopathies received genetic counseling, which was usually offered by the ophthalmologist. Referrals to the genetic service consisted of 25% of the cases. The variable genetic couseling, together with others such as female sex and those having a higher educational level, significantly influenced alterations in family planning. Although they had poor access to the establishment of stable conjugal unions, they had children in the same proportion as their normal siblings. This fact underscores the importance of genetic counseling. The therapeutic and preventive potential of genetic counseling in the prevention of blindness is not adequately used. Discussions on genetics held with Brazilian ophthalmologists and the community about the use of this potential, for the benefit of patients, through genetic counseling, should be more pragmatic and less theoretical<br>Mestrado<br>Oftalmologia<br>Mestre em Ciências Médicas

Genetic predisposition plays a major role in eye disorders, which could lead to blindness at different stages of life. Identification of novel variants and genes in eye disorders enhances the knowledge and understanding of the molecular pathology of these conditions. Through the GeneSEARCH project, a cohort has been established of consanguineous Iranian families to investigate various syndromic and non-syndromic inherited eye diseases. This specific study focused on 9 of these families presenting with features of Bardet Biedl syndrome, enhanced S- cone syndrome, retinitis pigmentosa, Leber congenital amaurosis, congenital cataract and exophthalmia. The initial ophthalmic examinations and phenotyping were carried out by clinical collaborators in Iran. Linkage analyses and autozygosity mapping were performed to identify the genomic regions most likely to contain the disease-causing gene. Whole exome and Sanger sequencing were performed to detect the causative mutation for each family. This study identifies five novel variants in the following genes: BBS5 (c.382C>G; Bardet Biedl Syndrome); CRB1 (c.361delC; retinitis pigmentosa); GUCY2D (c.2348T>C; Leber congenital amaurosis); FYCO1 (c.l056_1071delGGCCACACGGGACTCA; congenital cataract); and ZBTB11 (c.2708G>A; cataract and mental retardation). In addition, two previously reported variants were also identified in the following genes: NR2E3 (c.932G>A; enhanced S-cone syndrome) and ABCA4 (c.5461-10T>C; retinitis pigmentosa). Two loci associated with exophthalmia and mental retardation, and macular dystrophy were mapped on chromosome 4q24-q27 and chromosomel3ql3.3-ql4.2 respectively. ZBTB11 has not previously been reported as being associated with eye disease. ZBTB11 is thought to encode a transcription factor, but the identified mutation does not alter the functional localization of the protein in the nucleus. It may be possible that this mutation affects the transcriptional activity of the protein. This was supported by microarray analysis indicating reduced expression of BEST1 when comparing mutated ZBTB11 with wild type. Overall, the identification of genes will help the clinical diagnosis, management and genetic counselling in this population, and in the future will open the possibility of specific gene therapy and possible management.

Thesis (MSc)--Stellenbosch University, 2000.<br>ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are not taken. HH is often not considered as a cause of these conditions, particularly not in the elderly where the background frequencies of type II diabetes, osteoarthritis and heart failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in approximately 80% of affected individuals worldwide, has been linked to a raised incidence of malignancies of the colon and rectum, stomach and the haematological system. One of the highest carrier-frequencies (116) in the world for this mutation has been reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in approximately 1 in every 115 people in this group. A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype association studies. Their clinical presentation was denoted, biochemical iron-status determined and HFE genotyping performed. Either an increase or decrease in survival, or both, were proposed, depending on possible gender effects. HH has been positively associated with various cancer types, but may also protect against iron-deficiency anaemia which is by far the most frequent cause of anaemia in the older person. This study has led to the following findings: 1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population (similar in males and females), which is slightly lower than the 1/6 reported in younger adults from the same population. Only one C282Y homozygote and two C282YIH63D compound heterozygotes were detected, all of them female. 2. The prevalence of diabetes, heart disease, arthropathy or a combination of these conditions did not differ significantly in C282Y heterozygotes and the mutationnegative group. 3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was detected compared with two cases with rectal- and seven with colonic malignancies in 153 mutation-negative individuals. The single female C282Y homozygote identified suffered from both rectal and colon carcinoma and died approximately 6 months ago as a consequence of her colon malignancy. 4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in the elderly where a variety of factors that may influence the levels are often present in elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities. 5. Serum ferritin levels were lower than expected in elderly subjects with mutation C282Y and compound heterozygotes with both C282Y and H63D, which may be related to a variable penetrance of the HFE gene mutations. It is possible that variation in other genes exist that confer protection against iron-loading by gene-gene interaction. The probability that environmental factors (e.g. a low iron diet) are more important in this respect cannot be excluded, although this is considered less likely in the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant iron loading have died before reaching their seventies, particularly since none of the males included in this study were homozygous or compound heterozygous for the mutations analysed. In conclusion, possession of a mutant HFE gene does not appear to confer a survival advantage in old age, neither does it seem that mutation carriers with significant ironloading are overlooked by the medical fraternity. Further investigations are warranted to shed more light on the contributions of gene-gene and gene-environment interaction in the clinical manifestation of Hll, and how these processes can be manipulated to prevent the symptoms of this largely underdiagnosed disease.<br>AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is 'n outosomaal resessiewe yster-oorladingssiekte waar akkumulasie van yster in parenkimale organe kan lei tot suikersiekte, hartversaking, lewer sirrose, artropatie, moegheid en 'n verskeidenheid van ander probleme indien voorkomende maatreëls nie getref word nie. OH word gewoonlik nie oorweeg as moontlike oorsaak vir hierdie toestande nie, veral nie in ouer mense nie waar die agtergrond-frekwensie van tipe II diabetes, osteoartritis en hartversaking in elk geval hoog is. Heterosigositeit vir die HFE mutasie C282Y, wat OH veroorsaak in ongeveer 80% van geaffekteerde gevalle wêreldwyd, is geassosieer met 'n verhoogde voorkoms van kanker van die kolon, rektum, maag en ook die hematologiese sisteem. Van die hoogste draer frekwensies ter wêreld vir hierdie mutasie (1/6) is gevind in die Afrikaner populasie van Suid-Afrika, wat daarop dui dat 1 uit elke 115 mense in die groep homosigoties vir die C282Y mutasie kan wees. Eenhonderd sewe-en-negentig bejaarde Afrikaner vrywilligers het aan die studie deelgeneem wat daarop gemik was om genotipe/fenotipe korrelasies uit te voer. Die kliniese beeld van elke individu is gedokumenteer, die yster status biochemies bepaal en HFE genotipering uitgevoer. Die a priori veronderstelling was dat oorlewing sou toeneem of afneem, of beide, afhangende van die geslag van die individu. Daar is voorheen 'n verband gevind tussen OH en die ontwikkeling van bogenoemde maligniteite, maar aan die ander kant kan dit moontlik ook beskerm teen anemie as gevolg van yster gebrek, wat juis die mees algemene oorsaak van anemie in die ouer persoon is. Hierdie studie het tot die volgende bevindings gelei: 1. Die draer frekwensie van mutasie C282Y was 1/8 in die bejaardes (dieselfde in mans en vrouens), wat effens laer is as die 1/6 wat gerappoteer is in jonger volwassenes. Slegs een C282Y homosigoot en twee C282YIH63D saamgestelde heterosigote is opgespoor, en al drie was vroulik. 2. Die voorkoms van suikersiekte, hartsiekte, gewrigspyne of 'n kombinasie van hierdie aandoenings het nie betekenisvol verskil tussen die C282Y heterosigote en die mutasienegatiewe groep nie. 3. Daar was slegs een persoon met rektum karsinoom in die groep van 24 bejaarde C282Y heterosigote, terwyl daar twee gevalle met rektum kanker en sewe gevalle met kolon kanker gevind is onder die 153 mutasie-negatiewe individue. Die enkele vroulike C282Y homosigoot wat opgespoor is het beide rektum- en kolonkanker gehad en is ongeveer 6 maande vóór voltooing van die tesis oorlede aan haar kolon karsinoom. 4. Dit wil voorkom asof serum ferritien veral in bejaardes 'n hoogs onbetroubare maatstaf is vir yster status, aangesien dit deur 'n verskeidenheid faktore beïnvloed word wat dikwels in bejaardes aanwesig is as gevolg van veroudering of veelvuldige komorbiditeite. 5. Die serum ferritien vlakke was laer as verwag in sowel die bejaarde C282Y-homosigoot as in die twee saamgestelde heterosigote met mutasies C282Y en H63D, wat moonlik die gevolg is van die wisselende graad van penetrasie van HFE mutasies. Dit is moontlik dat variasie in ander gene beskerming bied teen yster-oorlading deur middel van geen-geen interaksie. Die moontlikheid dat omgewingsfaktore (soos 'n lae-yster dieet) 'n belangrike rol speel in hierdie verband kan nie uitgesluit word nie, hoewel dit minder waarskynlik lyk te wees in die lig van die feit dat dieselfde neiging waargeneem is in alle mutasie-positiewe bejaardes. Die kans is dus redelik groot dat individue met die C282Y mutasie en betekenisvolle yster oorlading oorlede is voordat hulle die sewentiger jare kon bereik, veral omdat geeneen van die mans wat ingesluit is in die studie homosigoot of 'n saamgestelde heterosigoot was vir die mutasies wat geanaliseer is nie. Opsommend wil dit voorkom asof die teenwoordigheid van 'n mutante HFE geen nie 'n beter oorlewingskans bied op ouer leeftyd nie, en dit blyk ook dat mutasie draers met betekenisvolle ysteroorlading nie deur dokters misgekyk word nie. Verdere navorsing is nodig om meer lig te werp op die bydrae van geen-geen- en geen-omgewing interaksie in die kliniese manifestasie van OH, en ook hoe hierdie prosesse gemanipuleer kan word om die simptome van hierdie onder -gediagnoseerde siekte te voorkom.

Inherited disorders are an important cause of physical handicap, deafness, mental retardation and blindness. There is considerable variation in the geographic and ethnic distribution of genetic disease due to biological pressures and historical accidents. In this context the relative prevalence of common inherited disorders and the recognition of rare conditions in isolated communities is of great academic importance. Oceanic islands are of special significance in the study of inherited disease. Virtually nothing has been documented concerning genetic disorders on the Island of Mauritius with a population of one million people. This study was undertaken to document the impact of inherited disorders on handicapping conditions in this community. As genetic disease concentrates in institutions, formal screening of all the schools for the deaf and blind, and the associations for the physically and mentally handicapped on Mauritius was undertaken. This involved a careful history, clinical examination and genealogical study, with radiographic, biochemical and ancillary testing performed where appropriate. Referral clinics were also established for the assessment of individuals and families known, or thought to be afflicted with abnormalities or handicap of a genetic origin. To ensure completeness, a similar survey was performed on Rodrigues, a neighbouring island, as this community is included under the responsibilities of the Mauritian Ministry of Health. Accumulated data concerning 681 patients were analysed. Genetic disorders accounted for disability in 265 individuals representing 38,6% of the causes of handicap. Of these persons 54 were deaf, 30 were blind, 99 were mentally retarded and 80 were physically handicapped. Several new entities, considered unique to the area and a consequence of either consanguinity or the founder effect, were documented. Karyotyping on selected individuals was undertaken in the laboratories of the Department of Human Genetics, University of Cape Town. A molecular genetic study of a large family with X-linked deafness of Nance, conducted by the same laboratory, revealed tight linkage with the probe pDP34; linkage analysis was performed on patients with Duchenne muscular dystrophy. The collation of these original data, the delineation of the new genetic conditions and an analysis of the results form the subject of this thesis and provide a basis for the future development of genetic services on Mauritius.

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.

The domestic dog, Canis lupus familiaris, has emerged as a model system for the study of human hereditary diseases. Of the approximately 450 hereditary diseases described in the dog, half have clinical presentations that are quite similar to specific human diseases. Understanding the genetic bases of canine hereditary diseases will not only complement comparative genetics studies but also facilitate selective breeding practices to reduce incidences in the dog. Whole genome screens have great potential to identify the marker(s) that segregate with canine hereditary diseases for which no reasonable candidate genes exist. The Minimal Screening Set-1 (MSS-1) was the first set of microsatellite markers described for linkage analysis in the dog and was, until recently, the best tool for genome screens. The MSS-2 is the most recently described screening set and offers increased density and more polymorphic markers. The first objective of this work was to develop tools to streamline genomic analyses in the study of canine hereditary diseases. This was achieved through the development of 1) multiplexing strategies for the MSS-1, 2) a multiplex of microsatellite markers for use in canine forensics and parentage assays and 3) chromosome-specific multiplex panels for the MSS-2. Multiplexing is the simultaneous amplification and analysis of markers and significantly reduces the expense and time required to collect genotype information. Pancreatic acinar atrophy (PAA) is a disease characterized by the degeneration of acinar cells of the exocrine pancreas and is the most important cause of exocrine pancreatic insufficiency (EPI) in the German Shepherd Dog (GSD). Although the prognosis for dogs having EPI is typically good with treatment, many dogs are euthanized because the owners are unable to afford the expensive enzyme supplements. The second objective of this work was to determine the mode of transmission of EPI in the GSD and conduct a whole genome screen for linkage. Two extended families of GSDs having PAA were assembled and used to determine the pattern of transmission. The results of this indicate that PAA is an autosomal recessive disease. The multiplexed MSS-1 was used to conduct an initial whole genome screen, although no markers were suggestive of linkage.

The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

The development of the vertebrate eye is tightly controlled by precise genetic regulations. From a single ocular primordium to bilateral eyes with complex structures and cell types, it requires intensive proliferation and migration for cells in both the ectoderm and mesoderm to accomplish ocular morphogenesis, and during this process cell differentiation and interaction takes place to establish the complex composition of ocular cell types and cellular connections. Genetic defects can lead to severe abnormalities in eye morphogenesis and cell differentiation during ocular development. A tremendous amount of work has been done to identify both intrinsic and extrinsic factors that regulate ocular development. However, much more work is needed to fully understand this complex process. Sox4 is known as a transcription activator that regulates cell survival and differentiation in multiple embryonic tissues during development. Evidence of its requirement during ocular development has recently emerged, but the mechanism by which Sox4 regulates ocular development is far from elucidated. Chapter 1 of this dissertation provides an overview of different stages in embryonic eye development and known genetic interactions during each stage. It also reviews recent knowledge about SoxC proteins and their roles in ocular development. Chapter 2 presents data characterizing the expression profile of the zebrafish sox4 co-orthologs, sox4a and sox4b, in the developing eye. Additionally, it presents data from morpholino-mediated sox4 knockdown in zebrafish, which indicate that Sox4 deficiency leads to defects in choroid fissure closure through elevation in the Hedgehog (Hh) signaling pathway. Sox4 knockdown causes upregulation of the Hh ligand indian hedgehog b (ihhb), which alters the proximal-distal boundary of the optic vesicle and inhibits choroid fissure closure. Chapter 3 presents data reporting the generation of sox4 mutant zebrafish lines using the CRISPR/Cas9 genome editing system. Characterization of one sox4a maternal zygotic (MZ) mutant line confirms Sox4’s role in negative regulation of Hh signaling and reveals new evidence that maternal and zygotic sox4 are both critical for ocular development. Chapter 4 presents data demonstrating that sox4 is required for rod photoreceptor neurogenesis. Rod photoreceptor terminal differentiation is delayed in both sox4 morphants and sox4 CRISPR mutants, while rod progenitor and precursor cells are properly specified. In Chapter 5, the roles of Sox4 in regulating ocular development are summarized based on the results, and implications of the results are discussed to expand our understanding of the genetic regulation of ocular morphogenesis and retinal neurogenesis.