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Ginsburg, David. "Genetic Modifiers of Thrombosis in Mice." Blood 114, no. 22 (November 20, 2009): SCI—44—SCI—44. http://dx.doi.org/10.1182/blood.v114.22.sci-44.sci-44.
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Abstract Abstract SCI-44 The genetic factors responsible for the highly variable clinical course of inherited bleeding disorders including von Willebrand disease and hemophilia are largely unknown. Similar factors are also likely to contribute to the variability of common thrombotic disorders, including factor V Leiden. Studies by our lab over the past 10 years have used the power of mouse genetics to identify genes contributing to this variability (referred to as ‘modifier‘ genes). By performing genetic crosses between inbred strains of mice with elevated plasma levels of von Willebrand Factor (VWF) and other strains with low levels, we have mapped a total of 6 genetic factors contributing to the control of murine plasma VWF levels. Similar studies in ADAMTS13-deficient mice are in progress aimed at characterizing genes modifying susceptibility thrombotic thrombocytopenic purpura. We have also conducted large scale mutagenesis studies in the mouse in an effort to identify larger numbers of genes contributing to thrombosis risk in the setting of Factor V Leiden, and most recently are extending this approach to similar genetic screens in zebrafish. Finally, recent advances in human genetics are expanding the potential opportunities for directly identifying bleeding and thrombosis modifier genes in humans. Disclosures No relevant conflicts of interest to declare.
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Mésinèle, Julie, Manon Ruffin, Loïc Guillot, and Harriet Corvol. "Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes." International Journal of Molecular Sciences 23, no. 22 (November 17, 2022): 14205. http://dx.doi.org/10.3390/ijms232214205.
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Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named “modifier genes”, influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.
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Butnariu, Lăcrămioara Ionela, Elena Țarcă, Elena Cojocaru, Cristina Rusu, Ștefana Maria Moisă, Maria-Magdalena Leon Constantin, Eusebiu Vlad Gorduza, and Laura Mihaela Trandafir. "Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine." Journal of Clinical Medicine 10, no. 24 (December 13, 2021): 5821. http://dx.doi.org/10.3390/jcm10245821.
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Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.
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Davidson, Courtney E., Qian Li, Gary A. Churchill, Lucy R. Osborne, and Heather E. McDermid. "Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans." Physiological Genomics 31, no. 2 (October 2007): 244–51. http://dx.doi.org/10.1152/physiolgenomics.00062.2007.
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Neural tube defects (NTDs), the second most common birth defect in humans, are multifactorial with complex genetic and environmental causes, although the genetic factors are almost completely unknown. In mice, >100 single gene mutations cause NTDs; however, the penetrance in many of these single gene mutant lines is highly dependent on the genetic background. We previously reported that a homozygous Cecr2 mutation on a BALB/c background causes exencephaly at a frequency of 74% compared with 0% on an FVB/N background. We now report that a major genetic modifier on chromosome 19, mapped using whole genome linkage analysis, increases the relative risk of exencephaly by 3.74 times in homozygous BALB embryos vs. BALB/FVB heterozygotes. Scanning electron microscopy revealed that the modifier does not affect the location of neural tube closure site 2, a known murine susceptibility factor for exencephaly. Crossing the Sp ( Splotch) mutation in the Pax3 gene onto the FVB/N background for two generations indicated that this resistant strain also decreases the penetrance of spina bifida. The chromosome 19 modifier region corresponds to a linkage region on human chromosome 10q25.3 mapped in a whole genome scan of human NTD families. Since the FVB/N genetic background affects susceptibility to both exencephaly and spina bifida, the human homolog of the chromosome 19 modifier locus may be a better candidate for human NTD susceptibility factors than genes that when mutated actually cause NTDs in mice.
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Shcherbakova, N. V., A. B. Zhironkina, V. Yu Voinova, R. A. Ildarova, and M. A. Shkolnikova. "Phenotypic variability and modifier variants in children with hereditary heart diseases." Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) 66, no. 3 (July 1, 2021): 12–19. http://dx.doi.org/10.21508/1027-4065-2021-66-3-12-19.
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Despite the recent achievements in searching for the causes of monogenic human diseases, there is still a massive gap in understanding the molecular causes of phenotypic variability. At the moment, it is evident that the pathogenic genetic variant often acts together with the other genetic and non-genetic factors that can reduce or, on the contrary, aggravate the severity of the disease. Thus, to completely understand the disease, we shall consider the entire set of mechanisms leading to the resulting phenotype. This paper reviews the current state of the art in identifying genetic and non-genetic phenotype modifiers for rare monogenic cardiovascular diseases.
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Hyun, Cheol Hwan, Chae Young Yoon, He-Jin Lee, and Seung-Jae Lee. "LRRK2 as a Potential Genetic Modifier of Synucleinopathies: Interlacing the Two Major Genetic Factors of Parkinson’s Disease." Experimental Neurobiology 22, no. 4 (December 30, 2013): 249–57. http://dx.doi.org/10.5607/en.2013.22.4.249.
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Alcaraz, Wendy A., Edward Chen, Phoebe Valdes, Eunnie Kim, Yuan Hung Lo, Jennifer Vo, and Bruce A. Hamilton. "Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice." Human Molecular Genetics 20, no. 19 (July 5, 2011): 3822–30. http://dx.doi.org/10.1093/hmg/ddr300.
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Pelucchi, Sara, Giulia Ravasi, Cristina Arosio, Mario Mauri, Rocco Piazza, Raffaella Mariani, and Alberto Piperno. "HIF1A: A Putative Modifier of Hemochromatosis." International Journal of Molecular Sciences 22, no. 3 (January 27, 2021): 1245. http://dx.doi.org/10.3390/ijms22031245.
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HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.
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Durán, Anyelo, David A. Priestman, Macarena Las Las Heras, Boris Rebolledo-Jaramillo, Valeria Olguín, Juan F. Calderón, Silvana Zanlungo, Jaime Gutiérrez, Frances M. Platt, and Andrés D. Klein. "A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids." International Journal of Molecular Sciences 24, no. 5 (March 3, 2023): 4915. http://dx.doi.org/10.3390/ijms24054915.
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Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.
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Tebbi, Cameron K. "Sickle Cell Disease, a Review." Hemato 3, no. 2 (May 30, 2022): 341–66. http://dx.doi.org/10.3390/hemato3020024.
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Sickle cell disease and its variants constitute the most common inherited blood disorders affecting millions of individuals worldwide. Significant information regarding the nature of the genetic mutations and modifier genes that result in increased or decreased severity of the disease are available. In recent years, detailed data regarding molecular genetics, pathophysiology, mechanisms for the development of symptoms and side effects of sickle cell disease have been published. The relationship of physiological changes, cellular interactions, coexisting coagulation disorders, effects of association with other genetic disorders and a number of intervening factors have been explored. New techniques for pre-conception, prenatal, in utero, and neonatal screening are available. Means for prediction of the severity of the disease, clinical course of the disorder, and prevention of some of its major complications have been developed. The effects of psychosocial and environmental factors have been explored. Various therapeutic strategies including bone marrow and stem cell transplantation are currently employed in the treatment of patients with sickle cell disease. Recent progress in understanding the molecular pathways controlling mammalian erythropoiesis and globin switching, as well as advances in genome engineering, particularly the gene-editing techniques, have opened a venue for genetic-based treatment of the disease. Currently, sickle cell disease is often associated with a high rate of complications and mortality. The development of new pharmacological agents, methods for gene therapy, and alterations and modification of the coexisting genetic factors and modifiers for treatment of the disease are encouraging.
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Banerjee, Surya, Shimshon Benji, Sarah Liberow, and Josefa Steinhauer. "Using Drosophila melanogaster To Discover Human Disease Genes: An Educational Primer for Use with “Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the Phospholipase D Pathway as a Potential Therapeutic Target”." Genetics 216, no. 3 (November 2020): 633–41. http://dx.doi.org/10.1534/genetics.120.303495.
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Since the dawn of the 20th century, the fruit fly Drosophila melanogaster has been used as a model organism to understand the nature of genes and how they control development, behavior, and physiology. One of the most powerful experimental approaches employed in Drosophila is the forward genetic screen. In the 21st century, genome-wide screens have become popular tools for identifying evolutionarily conserved genes involved in complex human diseases. In the accompanying article “Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the Phospholipase D Pathway as a Potential Therapeutic Target,” Kankel and colleagues describe a forward genetic modifier screen to discover factors that contribute to the severe neurodegenerative disease amyotrophic lateral sclerosis (ALS). This primer briefly traces the history of genetic screens in Drosophila and introduces students to ALS. We then provide a set of guided reading questions to help students work through the data presented in the research article. Finally, several ideas for literature-based research projects are offered as opportunities for students to expand their appreciation of the potential scope of genetic screens. The primer is intended to help students and instructors thoroughly examine a current study that uses forward genetics in Drosophila to identify human disease genes.
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Dokun, Ayotunde O., Lingdan Chen, Mitsuharu Okutsu, Charles R. Farber, Surovi Hazarika, W. Schuyler Jones, Damian Craig, et al. "ADAM12: a genetic modifier of preclinical peripheral arterial disease." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 5 (September 2015): H790—H803. http://dx.doi.org/10.1152/ajpheart.00803.2014.
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In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 ( ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.
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Denic, Miloje, Dragana Ignjatovic-Micic, Goran Stankovic, Ksenija Markovic, Sladjana Zilic, Vesna Lazic-Jancic, Pedro Chauque, et al. "Role of genetic resources from different geographic and climatic regions in simultaneous breeding for high quality protein maize (HQPM) and stress tolerance." Genetika 44, no. 1 (2012): 13–23. http://dx.doi.org/10.2298/gensr1201013d.
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Due to the low biological value of proteins of common maize, it was reinitiated breeding for high protein quality maize (HQPM) using three genetic systems, namely: opaque-2 gene, endosperm modifier genes and enhancer genes, which are increasing lysine and tryptophan content in opaque-2 background In order to alleviate effect of abiotic and biotic stress factors, the genotypes with tolerance to those factors were included. Genetic resources originating from North, Central and South America, then West, Central and Southern Africa and gene bank of Maize Research Institute ?Zemun Polje? were used. Combining breeding approaches in selection of genetic resources, field plot techniques and laboratory analysis, it was created large number of early QPM varieties, inbred lines and hybrids with modified endosperm and high yield potential under poor and good growing conditions. Created lines exhibited high combining ability in conventional and non-conventional hybrids. Yield trials showed that QPM hybrids are competing with commercial hybrids of common maize.
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Fucharoen, Suthat, Pranee Winichagoon, Orapan Sripichai, Thongperm Munkongdee, Chutima Kumkhaek, Kanjana Vichitumaros, Johanna Whiacre, Ken Abel, and Andreas Braun. "Genetic Analysis of Candidate Modifier Polymorphisms in β-Thalassemia/Hb E Patients." Blood 104, no. 11 (November 16, 2004): 3781. http://dx.doi.org/10.1182/blood.v104.11.3781.3781.
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Abstract β-Thalassemia/Hb E patients encompass a number of clinical severities, ranging from nearly asymptomatic to transfusion-dependent thalassemia major. This has been well documented, but the causes of the variability and the molecular basis of the interaction remain unexplained. In general any factor capable of reducing the degree of alpha-globin-beta-globin chain imbalance will result in a milder form of thalassemia. The major modifying factors demonstrated in the mild cases are coinheritance of mild β+-thalassemia and Hb E genes, coinheritance of α-thalassemia and increased production of Hb F. However, the fact that many patients who have seemingly identical genotypes, β0-thalassemia/Hb E, and do not have a detectable α-thalassemia or increased Hb F production still have mild clinical symptoms, while other patients have a very severe clinical condition similar to homozygous β0-thalassemia. This variation suggests that other unknown modifying genetic factors may contribute to severity of the disease. To assess the relative contribution of genetic factors in the variation of severity among β-thalassemia/Hb E patients, we conducted a prospective study searching for modifying factors in almost 1100 Thai/Chinese β0-thalassemia/Hb E patients from Thailand using an automated, chip-based platform based on mass spectrometry (Sequenom’s MassARRAYTM system). A map of ~80 single nucleotide polymorphisms (SNPs) has been constructed spanning more than 80 kb, including the locus control region (LCR) and all beta-like globin genes. These SNPs were identified through resequencing and from the public domain, including well-characterized restriction fragment length polymorphisms (RFLPs) used in prior haplotype studies. Included in this panel are assays for polymorphic sites reported to influence globin gene expression, specifically Gγ-Xmn I polymorphism and BP-1 binding site upstream of β-globin gene. Genotyping of other candidate modifier loci, including SNPs in genes encoding alpha hemoglobin stabilizing protein (AHSP), β-globin gene repressor BP-1 protein, erythropoietin (Epo), and transcription factors; GATA-1, EKLF, NF-E2, has been studied. To identify additional modifier loci, carefully selected patient sub-groups representing the extremes in disease severity either mild or severe have been selected for DNA pool construction to be used in a genomewide screen involving up to 100,000 validated gene-based SNPs. It is expected that this genomewide screen will yield important information on the role of candidate genes and may uncover the association of novel polymorphisms with severity heterogeneity in β-thalassemia/Hb E disease.
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Spitali, Pietro, Irina Zaharieva, Stefan Bohringer, Monika Hiller, Amina Chaouch, Andreas Roos, Chiara Scotton, et al. "TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy." European Journal of Human Genetics 28, no. 6 (January 2, 2020): 815–25. http://dx.doi.org/10.1038/s41431-019-0563-6.
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AbstractDuchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.
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Tang, Jie, Niu Li, Guoqiang Li, Jian Wang, Tingting Yu, and Ruen Yao. "Assessment of Rare Genetic Variants to Identify Candidate Modifier Genes Underlying Neurological Manifestations in Neurofibromatosis 1 Patients." Genes 13, no. 12 (November 26, 2022): 2218. http://dx.doi.org/10.3390/genes13122218.
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Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype–phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including CUL7, DPH1, and BCO1 are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1.
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Iwakawa, Hidekazu, Hiro Takahashi, Yasunori Machida, and Chiyoko Machida. "Roles of ASYMMETRIC LEAVES2 (AS2) and Nucleolar Proteins in the Adaxial–Abaxial Polarity Specification at the Perinucleolar Region in Arabidopsis." International Journal of Molecular Sciences 21, no. 19 (October 3, 2020): 7314. http://dx.doi.org/10.3390/ijms21197314.
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Leaves of Arabidopsis develop from a shoot apical meristem grow along three (proximal–distal, adaxial–abaxial, and medial–lateral) axes and form a flat symmetric architecture. ASYMMETRIC LEAVES2 (AS2), a key regulator for leaf adaxial–abaxial partitioning, encodes a plant-specific nuclear protein and directly represses the abaxial-determining gene ETTIN/AUXIN RESPONSE FACTOR3 (ETT/ARF3). How AS2 could act as a critical regulator, however, has yet to be demonstrated, although it might play an epigenetic role. Here, we summarize the current understandings of the genetic, molecular, and cellular functions of AS2. A characteristic genetic feature of AS2 is the presence of a number of (about 60) modifier genes, mutations of which enhance the leaf abnormalities of as2. Although genes for proteins that are involved in diverse cellular processes are known as modifiers, it has recently become clear that many modifier proteins, such as NUCLEOLIN1 (NUC1) and RNA HELICASE10 (RH10), are localized in the nucleolus. Some modifiers including ribosomal proteins are also members of the small subunit processome (SSUP). In addition, AS2 forms perinucleolar bodies partially colocalizing with chromocenters that include the condensed inactive 45S ribosomal RNA genes. AS2 participates in maintaining CpG methylation in specific exons of ETT/ARF3. NUC1 and RH10 genes are also involved in maintaining the CpG methylation levels and repressing ETT/ARF3 transcript levels. AS2 and nucleolus-localizing modifiers might cooperatively repress ETT/ARF3 to develop symmetric flat leaves. These results raise the possibility of a nucleolus-related epigenetic repression system operating for developmental genes unique to plants and predict that AS2 could be a molecule with novel functions that cannot be explained by the conventional concept of transcription factors.
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Vink, Jacqueline M., Dorret I. Boomsma, Sarah E. Medland, Marleen H. M. de Moor, Janine H. Stubbe, Belinda K. Cornes, Nicholas G. Martin, et al. "Variance Components Models for Physical Activity With Age as Modifier: A Comparative Twin Study in Seven Countries." Twin Research and Human Genetics 14, no. 1 (February 1, 2011): 25–34. http://dx.doi.org/10.1375/twin.14.1.25.
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Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.
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Dove, William F., Robert T. Cormier, Karen A. Gould, Richard B. Halberg, Anita J. Merritt, Michael A. Newton, and Alexander R. Shoemaker. "The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 353, no. 1370 (June 29, 1998): 915–23. http://dx.doi.org/10.1098/rstb.1998.0256.
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The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc , the mouse homologue of the human adenomatous polyposis coli ( APC ) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild–type Apc allele; to interstitial deletions surrounding the wild–type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two–hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc . One of these, Mom1 , has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non–autonomous: when tumours arise in Mom1 heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post–mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1 , other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.
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RAO, MADHAVI, SAVITHA RAO, and LAKSHMIPRASAD JADHAV. "Genetic predisposition, Penetrance and Expressivity: An understanding through Prakriti and Vikara vighata bhava." Journal of Research and Education in Indian Medicine 29, no. 2 (2023): 1. http://dx.doi.org/10.5455/jreim.82-1614158677.
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Abstract Introduction: Biological inheritance, the process that makes an offspring acquire or become predisposed to characteristics of its parent can be understood in terms of prakriti. The determination of prakriti is dependent on the utkata dosha during the samyoga of shukra and shonita.1 The process of genetic coding begins at fertilization, DNA replicate with each dividing cell to carry the inherited information. Materials and methods: Construction of this article was done utilizing the concepts of Prakriti and Vikara vighata bhava stated in the Ayurveda samhitas. The basics of genetics were adopted from the available literature through books and published works. Results: The present article provides a theoretical review of the concept of genetic predisposition, disease occurrence and variable presentation. Discussion: Penetrance and expressivity of a particular trait is dependent on various factors like modifier genes, epigenetic factors or the environment. The non-occurrence & occurrence of diseases, get similarly affected by the presence or absence of vikara vighatakara bhava2 respectively. Conclusion: Thus the concepts of genetics can be imbibed into the concepts of prakriti & vikara vighata bhava. Key words: Expressivity, Penetrance, Prakriti, Vikara vighatakara bhava
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Bhattacharyya, Saumitri, Michael L. Rolfsmeier, Michael J. Dixon, Kara Wagoner, and Robert S. Lahue. "Identification of RTG2 as a Modifier Gene for CTG·CAG Repeat Instability in Saccharomyces cerevisiae." Genetics 162, no. 2 (October 1, 2002): 579–89. http://dx.doi.org/10.1093/genetics/162.2.579.
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Abstract Trinucleotide repeats (TNRs) undergo frequent mutations in families affected by TNR diseases and in model organisms. Much of the instability is conferred in cis by the sequence and length of the triplet tract. Trans-acting factors also modulate TNR instability risk, on the basis of such evidence as parent-of-origin effects. To help identify trans-acting modifiers, a screen was performed to find yeast mutants with altered CTG·CAG repeat mutation frequencies. The RTG2 gene was identified as one such modifier. In rtg2 mutants, expansions of CTG·CAG repeats show a modest increase in rate, depending on the starting tract length. Surprisingly, contractions were suppressed in an rtg2 background. This creates a situation in a model system where expansions outnumber contractions, as in humans. The rtg2 phenotype was apparently specific for CTG·CAG repeat instability, since no changes in mutation rate were observed for dinucleotide repeats or at the CAN1 reporter gene. This feature sets rtg2 mutants apart from most other mutants that affect genetic stability both for TNRs and at other DNA sequences. It was also found that RTG2 acts independently of its normal partners RTG1 and RTG3, suggesting a novel function of RTG2 that helps modify CTG·CAG repeat mutation risk.
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Bukaeva, Anna, Alexandra Ershova, Maria Kharlap, Anna Kiseleva, Vladimir Kutsenko, Evgeniia Sotnikova, Mikhail Divashuk, et al. "The Yield of Genetic Testing and Putative Genetic Factors of Disease Heterogeneity in Long QT Syndrome Patients." International Journal of Molecular Sciences 25, no. 22 (November 7, 2024): 11976. http://dx.doi.org/10.3390/ijms252211976.
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Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.
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Lillycrop, K. A., and G. C. Burdge. "Maternal diet as a modifier of offspring epigenetics." Journal of Developmental Origins of Health and Disease 6, no. 2 (April 2015): 88–95. http://dx.doi.org/10.1017/s2040174415000124.
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There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities.
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Yu, Meigen, Hui Ye, Ruth B. De-Paula, Carl Grant Mangleburg, Timothy Wu, Tom V. Lee, Yarong Li, et al. "Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity." PLOS Genetics 19, no. 5 (May 18, 2023): e1010760. http://dx.doi.org/10.1371/journal.pgen.1010760.
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Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson’s disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.
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Pastana, Lucas Favacho, Thays Amâncio Silva, Laura Patrícia Albarello Gellen, Giovana Miranda Vieira, Letícia Almeida de Assunção, Luciana Pereira Colares Leitão, Natasha Monte da Silva, et al. "The Genomic Profile Associated with Risk of Severe Forms of COVID-19 in Amazonian Native American Populations." Journal of Personalized Medicine 12, no. 4 (April 1, 2022): 554. http://dx.doi.org/10.3390/jpm12040554.
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Genetic factors associated with COVID-19 disease outcomes are poorly understood. This study aimed to associate genetic variants in the SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, and ABO genes with the risk of severe forms of COVID-19 in Amazonian Native Americans, and to compare the frequencies with continental populations. The study population was composed of 64 Amerindians from the Amazon region of northern Brazil. The difference in frequencies between the populations was analyzed using Fisher’s exact test, and the results were significant when p ≤ 0.05. We investigated 64 polymorphisms in 7 genes; we studied 47 genetic variants that were new or had impact predictions of high, moderate, or modifier. We identified 15 polymorphisms with moderate impact prediction in 4 genes (ABO, CXCR6, FYCO1, and SLC6A20). Among the variants analyzed, 18 showed significant differences in allele frequency in the NAM population when compared to others. We reported two new genetic variants with modifier impact in the Amazonian population that could be studied to validate the possible associations with COVID-19 outcomes. The genomic profile of Amazonian Native Americans may be associated with protection from severe forms of COVID-19. This work provides genomic data that may help forthcoming studies to improve COVID-19 outcomes.
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Rettew, David C., Jacqueline M. Vink, Gonneke Willemsen, Alicia Doyle, James J. Hudziak, and Dorret I. Boomsma. "The Genetic Architecture of Neuroticism in 3301 Dutch Adolescent Twins as a Function of Age and Sex: A Study From the Dutch Twin Register." Twin Research and Human Genetics 9, no. 1 (February 1, 2006): 24–29. http://dx.doi.org/10.1375/twin.9.1.24.
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AbstractThe objective of this study was to estimate the magnitude of genetic and environmental influences to variation in adolescent neuroticism as a function of age and sex. Neuroticism was assessed using the Amsterdamse Biografische Vragenlijst (ABV): a self-report personality instrument similar in content to the Eysenck Personality Questionnaire. Genetic modeling procedures, including age as modifier, were fitted to the total sample of 3301 Dutch adolescent twins aged 12 to 17 years (mean age 15.5). Significant influences of additive genetic factors (.59, 95% confidence intervals [CI] .54–.63) and unshared environmental factors (.41, 95% CI .37–.45) were found. Our data did not support a role of shared environment. Results showed that different genes may influence variation in neuroticism between girls and boys. No interaction was found between the variance components and age. Results generally support prior findings in adults and young children that neuroticism is influenced principally by additive genetic and unique environmental factors. The magnitude of the genetic component appears higher in the present sample of adolescents than in most studies of adults. The present study suggests that, in adolescence, different genes are expressed in boys and girls.
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Buettner, Manuela, and André Bleich. "Mapping colitis susceptibility in mouse models: distal chromosome 3 contains major loci related to Cdcs1." Physiological Genomics 45, no. 20 (October 15, 2013): 925–30. http://dx.doi.org/10.1152/physiolgenomics.00084.2013.
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Inflammatory bowel disease (IBD) summarizes a group of chronic intestinal disorders with Crohn's disease and ulcerative colitis being most prominent. Though much effort is put into identification of causative factors, its etiology is still not understood. Risk factors for disease development include genetic predisposition and environmental triggers. Crucial for identification and analysis of relevant factors are mouse models. Experimental IBD in mice occurs spontaneously or is induced by chemicals, cell transfer, pathogens, or genetic mutation. These models were utilized for analyzing genetic contribution to disease and genotype-environmental interactions. In these studies, a variety of modifier loci were identified, thereby demonstrating the complexity of disease. A major contribution of distal chromosome 3 was independently replicated in several studies. The first colitogenic QTL in this region was detected using the IL-10-deficient mouse model and called cytokine deficiency-induced colitis susceptibility ( Cdcs) 1. This quantitative trait locus contains at least three subintervals with independent genetic factors. This locus or defined subintervals were replicated in at least seven studies, using models based on dysregulation of innate or adaptive immunity or pathogen control. In this review we illustrate the various models used for genetic mapping of susceptibility to experimental IBD and display Cdcs1-related loci as well as the mechanism of their contribution identified so far.
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Orkin, Stuart H., and Daniel E. Bauer. "Emerging Genetic Therapy for Sickle Cell Disease." Annual Review of Medicine 70, no. 1 (January 27, 2019): 257–71. http://dx.doi.org/10.1146/annurev-med-041817-125507.
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The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.
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Valcárcel-Ocete, Leire, Gorka Alkorta-Aranburu, Mikel Iriondo, Asier Fullaondo, María García-Barcina, José Manuel Fernández-García, Elena Lezcano-García, et al. "Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene." PLOS ONE 10, no. 7 (July 6, 2015): e0131573. http://dx.doi.org/10.1371/journal.pone.0131573.
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Hendig, Doris, Marius Arndt, Christiane Szliska, Knut Kleesiek, and Christian Götting. "SPP1 Promoter Polymorphisms: Identification of the First Modifier Gene for Pseudoxanthoma Elasticum." Clinical Chemistry 53, no. 5 (May 1, 2007): 829–36. http://dx.doi.org/10.1373/clinchem.2006.083675.
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Abstract Background: Progressive calcification and fragmentation of elastic fibers are characteristic hallmarks of pseudoxanthoma elasticum (PXE), which is caused by mutations in ABCC6 encoding multidrug resistance–associated protein 6 (MRP6). Because of the great clinical variability of PXE, secondary genetic risk factors are suspected to exist. We investigated whether SPP1 (secreted phosphoprotein 1; previously OPN, osteopontin) promoter polymorphisms are associated with PXE. Methods: We screened an ∼2-kb region spanning the theoretical promoter of the SPP1 gene for sequence variations by denaturing HPLC and direct sequencing in 93 PXE patients. Sequence variations with a prevalence >5% were genotyped in 93 age- and sex-matched healthy controls. Statistical and haplotype association analyses were performed using Fisher exact test, PHASE v2.1.1, and Haploview 3.2. Results: Mutational screening revealed 9 different sequence variations. Three SPP1 promoter polymorphisms (c.−1748A>G, c.−155_156insG, and c.244_245insTG) were significantly more frequent in PXE patients than in 93 age- and sex-matched healthy controls (Pcorrected < 0.05 each). The odds ratios (95% CI) for PXE among carriers of the 3 alleles were, respectively, 2.16 (1.34–3.48), 2.41 (1.51–3.82), and 1.97 (1.23–3.15). Haplotype analysis of 6 SPP1 promoter polymorphisms revealed 1 haplotype to be significantly reduced among PXE patients (Pcorrected = 0.035, odds ratio 1.80, 95% CI 1.19–2.71). Conclusions: Polymorphisms in the SPP1 promoter are secondary genetic risk factors contributing to PXE susceptibility.
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Leggatt, Gary P., Eleanor G. Seaby, Kristin Veighey, Christine Gast, Rodney D. Gilbert, and Sarah Ennis. "A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases." Genes 14, no. 8 (August 3, 2023): 1582. http://dx.doi.org/10.3390/genes14081582.
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With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).
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Teoh, Jeffrey, Alyssa L. Gillespie, Heather Lee, Jessica Prince, Michael D. Stadnisky, Monique Anderson, William T. Nash, et al. "Genomic modifiers of natural killer cells, immune responsiveness and lymphoid tissue remodeling together increase host resistance to viral infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 61.3. http://dx.doi.org/10.4049/jimmunol.196.supp.61.3.
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Abstract The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.
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Finberg, Karin E., Rebecca Whittlesey, Mark D. Fleming, and Nancy C. Andrews. "Tmprss6 Is a Genetic Modifier of the Hfe-Hemochromatosis Phenotype in Mice." Blood 114, no. 22 (November 20, 2009): 625. http://dx.doi.org/10.1182/blood.v114.22.625.625.
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Abstract Abstract 625 HFE-associated hereditary hemochromatosis is an autosomal recessive disorder characterized by inappropriately elevated absorption of dietary iron by the gastrointestinal mucosa, resulting in excessive storage of iron in multiple organs. A significant proportion of individuals who are homozygous for HFE mutations fail to develop clinical symptoms, suggesting that environmental and/or genetic factors may influence the penetrance of this disorder. In vitro and animal studies have revealed that HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that acts to inhibit iron absorption by the duodenum. In contrast, TMPRSS6, a transmembrane serine protease produced by the liver, acts to inhibit hepcidin expression; both humans and mice harboring TMPRSS6 mutations display impaired intestinal iron absorption, resulting in a phenotype of iron-refractory iron deficiency anemia (IRIDA). Here we asked if heterozygous or homozygous loss of Tmprss6 function could modify the iron overload phenotype of Hfe null (Hfe-/-) mice, a mouse model of human HFE-hemochromatosis. To test this, we bred Hfe-/- mice to Tmprss6-/- mice; the latter harbor a targeted disruption of the Tmprss6 serine protease domain and exhibit an IRIDA phenotype. We generated Hfe-/-Tmprss6+/+, Hfe-/-Tmprss6+/-, and Hfe-/-Tmprss6-/- female mice (6-10 mice per genotype), in which parameters of systemic iron homeostasis were compared at eight weeks of age by Student's t test. Consistent with previous study of Hfe-/- mice, Hfe-/- mice harboring two wild type Tmprss6 alleles (Hfe-/-Tmprss6+/+ mice) showed serum iron concentration, transferrin saturation, and hepatic non-heme iron content that were significantly elevated compared to wild type mice of similar genetic background. Heterozygosity for Tmprss6 mutation, however, markedly reduced the severity of the hemochromatosis phenotype of Hfe-/- mice. Compared to Hfe-/- mice with two wild type Tmprss6 alleles, Hfe-/- mice that were heterozygous for Tmprss6 mutation (Hfe-/-Tmprss6+/- mice) showed significant reductions in serum iron concentration (p<0.01), transferrin saturation (p<0.005), and non-heme iron content of liver (p<10-4). Furthermore, homozygosity for Tmprss6 mutation completely ameliorated the iron overload phenotype of Hfe-/- mice and in fact led to systemic iron deficiency. Compared to both Hfe-/-Tmprss6+/+ and Hfe-/-Tmprss6+/- mice, Hfe-/-Tmprss6-/- mice showed markedly reduced serum iron concentration (p<10-7), transferrin saturation (p<10-10), and non-heme iron content of liver (p<10-4). Hfe-/-Tmprss6-/- mice also displayed iron deficiency anemia and appeared phenotypically similar to previously characterized Tmprss6-/- mice harboring two wild type copies of Hfe. In summary, these results demonstrate that Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. These findings suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-hemochromatosis and raise the possibility that pharmacological inhibition of TMPRSS6 activity might prove an effective therapy in this disorder. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Jiahui, Changming Zhang, Erzhi Gao, and Qing Zhou. "Next-Generation Sequencing-Based Genetic Diagnostic Strategies of Inherited Kidney Diseases." Kidney Diseases 7, no. 6 (2021): 425–37. http://dx.doi.org/10.1159/000519095.
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<b><i>Background:</i></b> At least 10% of adults and most of the children who receive renal replacement therapy have inherited kidney diseases. These disorders substantially decrease their life quality and have a large effect on the health-care system. Multisystem complications, with typical challenges for rare disorders, including variable phenotypes and fragmented clinical and biological data, make genetic diagnosis of inherited kidney disorders difficult. In current clinical practice, genetic diagnosis is important for clinical management, estimating disease development, and applying personal treatment for patients. <b><i>Summary:</i></b> Inherited kidney diseases comprise hundreds of different disorders. Here, we have summarized various monogenic kidney disorders. These disorders are caused by mutations in genes coding for a wide range of proteins including receptors, channels/transporters, enzymes, transcription factors, and structural components that might also have a role in extrarenal organs (bone, eyes, brain, skin, ear, etc.). With the development of next-generation sequencing technologies, genetic testing and analysis become more accessible, promoting our understanding of the pathophysiologic mechanisms of inherited kidney diseases. However, challenges exist in interpreting the significance of genetic variants and translating them to guide clinical managements. Alport syndrome is chosen as an example to introduce the practical application of genetic testing and diagnosis on inherited kidney diseases, considering its clinical features, genetic backgrounds, and genetic testing for making a genetic diagnosis. <b><i>Key Messages:</i></b> Recent advances in genomics have highlighted the complexity of Mendelian disorders, which is due to allelic heterogeneity (distinct mutations in the same gene produce distinct phenotypes), locus heterogeneity (mutations in distinct genes result in similar phenotypes), reduced penetrance, variable expressivity, modifier genes, and/or environmental factors. Implementation of precision medicine in clinical nephrology can improve the clinical diagnostic rate and treatment efficiency of kidney diseases, which requires a good understanding of genetics for nephrologists.
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Martínez-Campelo, Laura, Raquel Cruz, Alejandro Blanco-Verea, Isabel Moscoso, Eva Ramos-Luis, Ricardo Lage, María Álvarez-Barredo, et al. "Searching for genetic modulators of the phenotypic heterogeneity in Brugada syndrome." PLOS ONE 17, no. 3 (March 1, 2022): e0263469. http://dx.doi.org/10.1371/journal.pone.0263469.
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In Brugada syndrome, even within the same family where all affected individuals share the same mutation, phenotypic variation is prominent, with variable penetrance and expressivity, presenting different degrees of involvement. It is difficult to establish a direct correlation between genotype and phenotype to predict prognosis in complications and risk of sudden death. The factors that modulate this inter- and intra-familial phenotypic variability remain to be determined. With the intention of testing whether other genetic factors, in addition to the causal mutation in SCN5A, may have a modulating effect on the Brugada phenotype and the risk of sudden death, we have studied 8 families with a causal variant in SCN5A with at least two affected individuals, one of whom has suffered cardiac arrest or sudden death. Whole exome sequencing was performed looking for additional variants that modify the phenotype and allow us to predict a better or worse prognosis for the evolution of the disease. The results did not show any clear genetic modifier; nevertheless, highlight the possible implication of the cholesterol and fibrosis pathways, as well as the circadian rhythm, as possible modulators of Brugada syndrome phenotype.
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Mehmood, Gulrukh, Abid Sohail Taj, Arshi Naz, and Tariq Masood Khan. "Molecular Characterization and Frequencies of Different Genetic Ameliorating Factors in Transfusion Dependent Thalassemia Patients from District Peshawar." Blood 134, Supplement_1 (November 13, 2019): 4816. http://dx.doi.org/10.1182/blood-2019-130049.
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Background Thalassemia is one of the most common genetic blood disorders worldwide. The carrier rate of β thalassemia in Pakistan is found to be around 5-7%, rendering it a major health concern. Approximately 5000 children are diagnosed with thalassemia major every year in Pakistan due to consanguineous marriages. More than 200 causative molecular defects have been identified in β-globin genes. About 20 mutations account for 90% of the abnormal β-genes. Clinical severity of β-thalassemia is modified by different factors. The important ones include the type of disease causing mutation and the ability to produce α and γ globin chains. A better understanding of these ameliorating factors may have a significant impact on disease management. Objectives 1. To re-assess diagnoses among local multi-transfused thalassemia syndrome patients. 2. To determine frequency of various genetic determinants of milder phenotypes of thalassemia among study patients. Methods Transfusion dependent thalassemia patients, upto 15 years age, were enrolled from Fatimid Foundation, Peshawar Pakistan. A comprehensive questionnaire encompassing demographic and clinical data was filled out for each patient. Genetic analyses for 2 alpha (α) and 13 prevalent beta (β) gene mutations and for polymorphisms at Xmn1-HBG2 and BCL11A were carried out on blood samples of the patients at National Institute of Blood Diseases, Karachi Pakistan. The data collected was analysed at Khyber Medical University (KMU) Peshawar Pakistan. Results A total of 54 transfusion dependent thalassemia patients were enrolled into the study. Homozygous or compound heterozygous combinations of β-globin gene mutations were identified in all the study patients. Eleven patients were found to have a co-existing heterozygous α (3.7kb) deletion, two patients had Xmn1-HBG2 polymorphism and 38 had BCL11A polymorphism. Homozygous Fr 8-9 was the most frequent mutation, found in 19 (35.2%) patients. Only 13 patients were found to have isolated β-globin gene mutations. In total, 46 (85.2%) study patients were identified to have an ameliorating genetic factor (a co-existing α-globin gene mutation, an Xmn1-HBG2 polymorphism or a BCL11A polymorphism) besides the main β-globin gene mutation. Conclusion It was concluded that co-existing genetic ameliorating factors are frequently found in transfusion dependent β-thalassemia patients of Peshawar District. These factors impart a milder phenotype to an otherwise severe disease. It is hence suggested that β-thalassemia patients from District Peshawar be screened for these factors and due consideration be paid by the physician in devising management plans. Key Words Thalassemia, Genetic modifier in thalassemia, Transfusion dependent Anaemia, Xmn1 polymorphism Disclosures No relevant conflicts of interest to declare.
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Hardouin, Giulia, Elisa Magrin, Alice Corsia, Marina Cavazzana, Annarita Miccio, and Michaela Semeraro. "Sickle Cell Disease: From Genetics to Curative Approaches." Annual Review of Genomics and Human Genetics 24, no. 1 (August 25, 2023): 255–75. http://dx.doi.org/10.1146/annurev-genom-120122-081037.
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Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for β-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)] polymerizes under low-oxygen conditions and causes red blood cells to sickle. The clinical presentation varies from very severe (with acute pain, chronic pain, and early mortality) to normal (few complications and a normal life span). The variability of SCD might be due (in part) to various genetic modulators. First, we review the main genetic factors, polymorphisms, and modifier genes that influence the expression of globin or otherwise modulate the severity of SCD. Considering SCD as a complex, multifactorial disorder is important for the development of appropriate pharmacological and genetic treatments. Second, we review the characteristics, advantages, and disadvantages of the latest advances in gene therapy for SCD, from lentiviral-vector-based approaches to gene-editing strategies.
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Ryan, Thomas M., Yongliang Huo, and Sean McConnell. "Global ENU Mutagenesis Screen for Genetic Modifiers in Sickle Cell Disease Mice." Blood 104, no. 11 (November 16, 2004): 3733. http://dx.doi.org/10.1182/blood.v104.11.3733.3733.
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Abstract Genetic modifiers of sickle cell disease (SCD) will be identified in an animal model of SCD after mutagenesis with the chemical mutagen N-ethyl-N-nitrosourea (ENU). This phenotype driven approach utilizes a third generation knock-in (KI) mouse model of SCD that reproduces most if not all of the pathology of the disorder. This model was produced by targeted gene replacement of the murine α-globin genes with human α-globin and the murine β globin genes with a human γ- and βs-globin gene cassette that mimics the fetal to adult hemoglobin switch that occurs in man. Sickle embryonic stem (ES) cells were derived from developing blastocysts isolated from female sickle mice that were mated with sickle males. Sickle ES cells were treated with ENU and a mutant library of independent subclones was established and archived. The optimal ENU dosage was empirically determined through a series of pilot experiments that measured the HPRT mutation frequency and the efficiency of producing sickle mice from the mutagenized cells by tetraploid embryo complementation. Animals harboring mutations that affect hematological indices, kidney function, or liver function are identified in the mutagenized sickle mice by comparison to cloned control sickle mice. Microsatellite linkage analyses of mutant offspring outcrossed to congenic SCD mice and direct sequence comparison to the murine genome will allow the positional cloning of modifier genes. Putative modifying factors will be positively confirmed by introducing the exact germline modification discovered during the ENU screen into the unmutagenized ES cells, followed by the direct examination of the phenotype in mice generated from the modified cells by cloning. These studies will define gene(s) responsible for the phenotypic variation in disease severity that is observed in the SCD population. By experimental design, the therapeutic benefit or detriment associated with each modifying gene(s) on the in vivo pathophysiology of sickle cell anemia will be tested directly in our animal model of this disorder.
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Grimes, H. Leighton, and Shane R. Horman. "A Gene Dosage Requirement for Transcription Factor Gfi1 in the Regulation of Myelopoiesis and Myeloproliferative Disorders." Blood 108, no. 11 (November 16, 2006): 4180. http://dx.doi.org/10.1182/blood.v108.11.4180.4180.
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Abstract The generation of mature myeloid lineage cells from hematopoietic stem cells (HSCs) requires a precise synergy between cytokine signaling and lineage-specific transcription factors. Gfi1 (Growth Factor Independence 1) is a zinc finger transcription factor that is necessary for normal myelopoiesis. Gfi1 knockout mice display an abnormal ratio of phenotypic common myeloid progenitors (CMP) and granulocyte/monocyte progenitors (GMP), and such mice completely lack mature neutrophils. In contrast, the Gfi1 heterozygote mouse presents no obvious phenotype. Here we show a gene dosage requirement for Gfi1 in the differentiation of mature myeloid cells. While bone marrow from wild type littermates generates granulocytic, monocytic and mixed methylcellulose colonies, Gfi1 knockout bone marrow cells yield mainly monocytic colonies. In comparison to wild type littermates, Gfi1+/− bone marrow cells generate lower numbers of granulocytic colonies and higher numbers of monocytic colonies. Interestingly, methylcellulose colonies from both Gfi1 knockout mice and heterozygotes display increased serial replating capacity in comparison to wild type littermates. These data suggest that Gfi1 gene dosage may control self renewal and may relate to oncogenic transformation. Activating mutations in K-Ras are common genetic abnormalities in human acute myeloid leukemia and myeloproliferative disease (MPD). However, expression of activated Ras from endogenous regulatory sequences (knock-in) results in an MPD of varying lethality. The severity of the K-Ras-induced MPD depends on unknown genetic modifiers, as lethality is increased in a Balb/c genetic background. Given the effect of Gfi1 gene dosage on serial replating, we have analyzed the effect of Gfi1 gene dosage on the activated Ras knock-in mouse model of MPD. Preliminary data indicate that lowering Gfi1 gene dosage modifies the phenotype of activated Ras MPD by dramatically increasing the number of immature circulating myeloid progenitors. These results reveal that Gfi1 is a modifier of Ras induced disease pathogenesis.
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Noble, NA, and G. Rothstein. "The Dpg gene: an intracorpuscular modifier of red cell metabolism." Blood 67, no. 5 (May 1, 1986): 1210–14. http://dx.doi.org/10.1182/blood.v67.5.1210.1210.
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Abstract The genetic locus designated Dpg has two alleles in outbred Long-Evans rats. Genotype at this locus affects quantities of red cell 2,3- diphosphoglycerate (DPG) and adenosine triphosphate, as well as activities of two important glycolytic enzymes: phosphofructokinase and pyruvate kinase. Intravascular red cell survival is shortened in low- DPG animals. In order to get closer to the specific action of this locus, we addressed the question of whether the Dpg gene acts through intracorpuscular or extracorpuscular factors. Bone marrow transplantation after total body irradiation and 51Cr red cell survival after cross transfusion were the methods used. Because the animals that were used differed in hemoglobin phenotype, donor and recipient cells could be quantified in cross-transplanted animals. Phenotypic markers of Dpg genotype were measured in animals 40 to 50 days after transplantation. Values for these markers correlated highly with the percentage of donor and recipient cells present. In vivo survival of low-DPG red cells was significantly shorter than that of high-DPG cells (P less than .05), regardless of the genotype of the recipient. From the present studies, we conclude that the action of the Dpg gene is exerted by an intracorpuscular factor.
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Noble, NA, and G. Rothstein. "The Dpg gene: an intracorpuscular modifier of red cell metabolism." Blood 67, no. 5 (May 1, 1986): 1210–14. http://dx.doi.org/10.1182/blood.v67.5.1210.bloodjournal6751210.
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The genetic locus designated Dpg has two alleles in outbred Long-Evans rats. Genotype at this locus affects quantities of red cell 2,3- diphosphoglycerate (DPG) and adenosine triphosphate, as well as activities of two important glycolytic enzymes: phosphofructokinase and pyruvate kinase. Intravascular red cell survival is shortened in low- DPG animals. In order to get closer to the specific action of this locus, we addressed the question of whether the Dpg gene acts through intracorpuscular or extracorpuscular factors. Bone marrow transplantation after total body irradiation and 51Cr red cell survival after cross transfusion were the methods used. Because the animals that were used differed in hemoglobin phenotype, donor and recipient cells could be quantified in cross-transplanted animals. Phenotypic markers of Dpg genotype were measured in animals 40 to 50 days after transplantation. Values for these markers correlated highly with the percentage of donor and recipient cells present. In vivo survival of low-DPG red cells was significantly shorter than that of high-DPG cells (P less than .05), regardless of the genotype of the recipient. From the present studies, we conclude that the action of the Dpg gene is exerted by an intracorpuscular factor.
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GUAY-WOODFORD, LISA M., CHRISTOPHER J. WRIGHT, GERD WALZ, and GARY A. CHURCHILL. "Quantitative Trait Loci Modulate Renal Cystic Disease Severity in the Mouse bpk Model." Journal of the American Society of Nephrology 11, no. 7 (July 2000): 1253–60. http://dx.doi.org/10.1681/asn.v1171253.
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Abstract. Numerous mouse models of polycystic kidney disease (PKD) have been described in which the mutant phenotypes closely resemble human PKD with regard to morphology, cyst localization, and disease progression. As in human PKD, genetic background affects the disease phenotype in mouse PKD models. Using experimental crosses, these modifying effects can be dissected into discrete genetic factors referred to as quantitative trait loci. The locus for the mouse bpk model was recently mapped to chromosome (Chr) 10. In the course of these studies, marked variability was observed in the renal cystic disease expressed in F2 bpk/bpk homozygotes of a (BALB/c-+/bpk × CAST/Ei)F1 intercross. The current study was undertaken to further characterize the renal cystic disease as quantitative trait in this F2 cohort and to map the genetic modifiers that modulate this phenotype. Whole-genome scans revealed a CAST-derived locus on distal Chr 6, near D6Mit14, that affects renal cystic disease severity. Additional analyses identified loci on Chr 1, Chr 2, and Chr 4, as well as a possible interaction between the Chr 6 locus and a locus on distal Chr 1, near D1Mit17. Interestingly, the gene encoding RGS7, a regulator of G protein signaling that binds to polycystin-1, was mapped to the same Chr 1 interval. It is concluded that the severity of the bpk renal cystic disease phenotype is modulated by multiple loci and possibly by epistatic interaction among them. It is hypothesized that the gene encoding the polycystin-binding partner RGS7 is a candidate for the Chr 1 genetic modifier.
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Hur, Yoon-Mi. "Genetic and Environmental Influences on Vigorous Exercise in South Korean Adolescent and Young Adult Twins." Twin Research and Human Genetics 24, no. 2 (March 19, 2021): 116–22. http://dx.doi.org/10.1017/thg.2021.6.
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AbstractTwin studies of physical exercise for Asian twins are sparse. This study aimed to examine genetic and environmental influences on frequency of vigorous exercise (FVE) in South Korean twins, with a special emphasis on sex effects. Telephone interviews on FVE were administered to 1757 twins (mean age = 19.05 years, SD = 3.01 years). Tetrachoric correlations were significantly different between monozygotic (MZ) and dizygotic (DZ) twins in males (.40 vs. .12), but they were similar in females (.44 vs. .45), suggesting the importance of genetic factors in FVE in males and that of common environmental factors in females. A scalar sex-limitation model incorporating age as a modifier was applied to data. The results revealed that genetic, common and individual environmental influences did not vary significantly with age, but differed across two sexes, confirming twin correlational analyses. In the best-fitting model, additive genetic and individual environmental influences on FVE were, respectively, .35 (95% CI [.26, .39]) and .65 (95% CI [.61, .74]) in males, and common and individual environmental influences were, respectively, .45 (95% CI [.35, .53]) and .55 (95% CI [.47, .65]) in females. These results contrasted starkly with recent findings from a large sample of Chinese adult twins (age >18 years), in which most variance (≥95%) of vigorous physical activity was attributable to common environmental influences in both sexes. Replications in other Asian samples are clearly needed.
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Lee, Soojin, Se Min Bang, Joon Woo Lee, and Kyoung Sang Cho. "Evaluation of Traditional Medicines for Neurodegenerative Diseases UsingDrosophilaModels." Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/967462.
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Drosophilais one of the oldest and most powerful genetic models and has led to novel insights into a variety of biological processes. Recently,Drosophilahas emerged as a model system to study human diseases, including several important neurodegenerative diseases. Because of the genomic similarity betweenDrosophilaand humans,Drosophilaneurodegenerative disease models exhibit a variety of human-disease-like phenotypes, facilitating fast and cost-effectivein vivogenetic modifier screening and drug evaluation. Using these models, many disease-associated genetic factors have been identified, leading to the identification of compelling drug candidates. Recently, the safety and efficacy of traditional medicines for human diseases have been evaluated in various animal disease models. Despite the advantages of theDrosophilamodel, its usage in the evaluation of traditional medicines is only nascent. Here, we introduce theDrosophilamodel for neurodegenerative diseases and some examples demonstrating the successful application ofDrosophilamodels in the evaluation of traditional medicines.
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Schmoellerl, Johannes, Romana Maerschalk, Martina Weissenboeck, Jasmin Ali, Thomas Köcher, Aleksandra Bundalo, Florian Andersch, et al. "Systematic Identification of Gene-Drug Interactions Using an Advanced CRISPR Screening Platform to Predict Therapy Response across Cancer Types." Blood 144, Supplement 1 (November 5, 2024): 2235. https://doi.org/10.1182/blood-2024-211758.
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Cancer entities and the presence or absence of genetic driver mutations often determine therapeutic trajectories for patients. However, the efficacy of chemotherapeutics and targeted therapies varies significantly and rarely induces long-term remissions due to the rapid emergence of therapy resistance. Consequently, there is an urgent need to identify response-predictive biomarkers that enable effective precision medicine. We hypothesized that, similar to genetic drivers that qualify patient subgroups for specific targeted therapeutics, genetic aberrations exist within cancer cells that confer intrinsic sensitivity to chemotherapeutics and small-molecule inhibitors lacking response-predictive biomarkers. To test this, we developed an advanced CRISPR/Cas9-based high-throughput screening platform to systematically interrogate gene-drug interactions of 18 clinically established and emerging therapeutics used for treating hematopoietic malignancies. These included antimetabolites, anthracyclines, hypomethylating agents, and various selective small-molecule inhibitors. Utilizing optimized sgRNA prediction algorithms and a dual-sgRNA design, we constructed low-complexity genome-wide sgRNA libraries that enhance the technical robustness and throughput of drug-modifier screens in culture and enable in vivo screens. We uncovered 180 genes including various established and previously unknown factors that upon knockout result in selective synergy or resistance to one of the 18 therapeutics. We functionally validated various gene-drug interactions in multiple leukemia and solid cancer cell lines, suggesting that the loss of these genes confers predictable drug response to specific compounds independent of the tissue context. As the mechanistic relationship of many gene-drug interactions was uncharted, we assessed their impact on drug metabolism using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). While several genes modified cellular drug influx/efflux or metabolism, many others altered drug sensitivity by distinct means that remain to be explored. However, integrating publicly available whole-exome sequencing data pinpointed patients across diverse cancer entities harboring homozygous deletions within selected genes that modify drug response, suggesting these patients could display predictable drug sensitivity. To test this in vivo, we probed three drug modifier genes (SAMHD1, XRCC4, and USP48) that are recurrently deleted in cancer patients using colorectal cancer cell line-derived xenotransplants and examined their response to Cytarabine, Doxorubicin, and Decitabine treatment, respectively. Strikingly, while wildtype colorectal cancer transplants were unresponsive, tumors with deletions in these genes were amenable to treatment, resulting in significant tumor control. Together, our data show that our scalable screening pipeline can systematically interrogate gene-drug interactions for a broad panel of drugs lacking response-predictive biomarkers. They suggest that integrating drug modifier genes in targeted exome sequencing panels of cancer patients may pave the way for discovering unexplored treatment opportunities.
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de Rojas, Itziar, Isabel Hernández, Laura Montrreal, Inés Quintela, Miguel Calero, Jose Luís Royo, Raquel Huerto Vilas, et al. "Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study." Journal of Personalized Medicine 11, no. 12 (December 7, 2021): 1318. http://dx.doi.org/10.3390/jpm11121318.
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Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.
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Luo, Na, Shun Mei Liu, Hong Liu, Qiong Li, Qun Xu, Xi Sun, Brandi Davis, Jing Li, and Streamson Chua. "Allelic Variation on Chromosome 5 Controls β-Cell Mass Expansion during Hyperglycemia in Leptin Receptor-Deficient Diabetes Mice." Endocrinology 147, no. 5 (May 1, 2006): 2287–95. http://dx.doi.org/10.1210/en.2005-0853.
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Leptin signaling is a critical component of normal insulin sensitivity. Overt hyperglycemia and type 2 diabetes mellitus can be manifested in states of leptin signaling deficiencies by the additional effects of other genetic factors. We have previously described the contrasting insulin sensitivities and glycemic states of two congenic diabetes (db/db) mouse strains. C57BL/6J db/db mice have mild insulin resistance and achieve euglycemia with mild hyperinsulinemia. FVB db/db mice have severe insulin resistance and are hyperglycemic despite escalating hyperinsulinemia with expanded pancreatic β-cell mass. Analysis of obese progeny from the two reciprocal backcrosses suggests that genetic modifiers for insulin sensitivity are separable from loci that modulate β-cell mass. A genome scan of the backcross to FVB suggests that one or more modifier genes are present on chromosome 5. This evidence is supported by the phenotypes of multiple incipient congenic strains wherein the hyperglycemia observed in obese FVB mice is reproduced. With similar degrees of hyperglycemia in obese mice of these strains, the haplotype at chromosome 5 is associated with β-cell mass and circulating insulin concentrations. Finally, we offer arguments that production of multiple incipient congenic lines is an economical alternative to the production of speed congenic strains.
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Merabet, Samir, Francoise Catala, Jacques Pradel, and Yacine Graba. "A Green Fluorescent Protein Reporter Genetic Screen That Identifies Modifiers of Hox Gene Function in the Drosophila Embryo." Genetics 162, no. 1 (September 1, 2002): 189–202. http://dx.doi.org/10.1093/genetics/162.1.189.
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Abstract Hox genes encode evolutionarily conserved transcription factors that play fundamental roles in the organization of the animal body plan. Molecular studies emphasize that unidentified genes contribute to the control of Hox activity. In this study, we describe a genetic screen designed to identify functions required for the control of the wingless (wg) and empty spiracles (ems) target genes by the Hox Abdominal-A and Abdominal-B proteins. A collection of chromosomal deficiencies were screened for their ability to modify GFP fluorescence patterns driven by Hox response elements (HREs) from wg and ems. We found 15 deficiencies that modify the activity of the ems HRE and 18 that modify the activity of the wg HRE. Many deficiencies cause ectopic activity of the HREs, suggesting that spatial restriction of transcriptional activity is an important level in the control of Hox gene function. Further analysis identified eight loci involved in the homeotic regulation of wg or ems. A majority of these modifier genes correspond to previously characterized genes, although not for their roles in the regulation of Hox targets. Five of them encode products acting in or in connection with signal transduction pathways, which suggests an extensive use of signaling in the control of Hox gene function.
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Joó, József Gábor. "Recent perspectives on the development of the central nervous system and the genetic background of neural tube defects." Orvosi Hetilap 150, no. 19 (May 2009): 873–82. http://dx.doi.org/10.1556/oh.2009.28564.
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Neural tube defects are rare and mostly lethal malformations. The pattern of inheritance of these malformations is multifactorial, rendering the identification of the underlying causes. Numerous studies have been conducted to elucidate the genetic basis of the development of the central nervous system. Essential signaling pathways of the development of the central nervous system include the planar cell polarity pathway, which is important for the initiation of neural tube closure as well as well as sonic hedhehog pathway, which regulates the neural plate bending. Genes and their mutations influencing the different stages of neurulation have been investigated for their eventual role in the development of these malformations. Among the environmental factors, folic acid seems to be the most important modifier of the risk of human neural tube defects. Genes of the folate metabolism pathways have also been investigated to identify mutations resulting in increased risk of NTDs. In this review the author has attempted to summarize the knowledge on neural tube defects, with special regard to genetic factors of the etiology.
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O'Meara, Caitlin C., Matthew Hoffman, William E. Sweeney, Shirng-Wern Tsaih, Bing Xiao, Howard J. Jacob, Ellis D. Avner, and Carol Moreno. "Role of genetic modifiers in an orthologous rat model of ARPKD." Physiological Genomics 44, no. 15 (August 1, 2012): 741–53. http://dx.doi.org/10.1152/physiolgenomics.00187.2011.
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Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset and severity of the disease. We report here for the first time that ARPKD susceptibility is attenuated by introgressing the mutated Pkhd1 disease allele from the polycystic kidney (PCK) rat onto the FHH (Fawn-Hooded Hypertensive) genetic background. Compared with PCK, the FHH .Pkhd1 strain had significantly decreased renal cyst formation that coincided with a threefold reduction in mean kidney weights. Further analysis revealed that the FHH. Pkhd1 is protected from increased blood pressure as well as elevated plasma creatinine and blood urea nitrogen levels. On the other hand, liver weight and biliary cystogenesis revealed no differences between PCK and FHH. Pkdh1, indicating that genes within the FHH genetic background prevent the development of renal, but not hepatic, manifestations of ARPKD. Microarray expression analysis of kidneys from 30-day-old PCK rats revealed increased expression of genes previously identified in PKD renal expression profiles, such as inflammatory response, extracellular matrix synthesis, and cell proliferation genes among others, whereas the FHH. Pkhd1 did not show activation of these common markers of disease. This newly developed strain can serve as a tool to map modifier genes for renal disease in ARPKD and provides further insight into disease variability and pathophysiology.