Gene modification research has potential, from diagnostic to therapeutic levels. The most promising metabolic pathways include the TGF-1 signaling system, inflammation and protein transport

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Product ◽  
Metabolic Pathways ◽  
Protein Transport ◽  
Genetic Modifier ◽  
Neuromuscular Diseases ◽  
Modifier Gene ◽  
Genetic Modifiers ◽  
Signaling System ◽  
Synonymous Mutations ◽  
Oligogenic Inheritance

A human disease modifier gene is a gene that regulates another gene's function or effects. The presence of a modifier gene is not sufficient to cause a disease. Nonetheless, the presence of a modifier gene alters the disease's onset and severity. A genetic modifier can interact in several ways with another gene product. Changes in penetration and expressiveness, direct interaction with the target gene product, mechanistic contribution to the same biological process and/or functional compensation through other routes might all have effects. Despite long hypothesized genetic modifiers, their influence is yet unclear. Improved computational tools, international consortia with larger patient cohorts, improved laboratory precision procedures, and high-throughput technology have all helped find and verify genetic modifiers in recent years. As new possible genetic modifiers are found, common pathways can be established linking some modifying genes or neuromuscular diseases. The most promising metabolic pathways include the TGF-1 signaling system, inflammation, endoplasmic reticulum metabolism, axon formation, regeneration, extracellular matrix, RNA metabolism and protein transport. Perhaps in the future, we will conceive of neuromuscular diseases in terms of impaired molecular processes and the amount involving multiple metabolic pathways, rather than main genetic variations or medical nomenclature. Another fascinating feature of genetic modifiers in neuromuscular diseases is the involvement of genetic moderators in oligogenic inheritance. Preliminary research on animal models and people indicates that more rare, non-synonymous mutations in NMD-related genes might worsen muscle damage and lead to a more severe phenotype. Besides oligogenic inheritance, the "diagnostic gap"—individuals who remain unresolved after exome or genome sequencing—can be explained by the action of genetic modifiers. In the coming years, genetic modification research is expected to advance from diagnostic to therapeutic levels, and it would be extremely tempting from a therapeutic point of view to identify "protective" modifiers and comparable metabolic pathways for NMDs.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

scholarly journals Oligogenic inheritance of a human heart disease involving a genetic modifier

Science ◽  
2019 ◽  
Vol 364 (6443) ◽  
pp. 865-870 ◽  
Author(s):  
Casey A. Gifford ◽  
Sanjeev S. Ranade ◽  
Ryan Samarakoon ◽  
Hazel T. Salunga ◽  
T. Yvanka de Soysa ◽  
...  
Keyword(s):  
Nuclear Family ◽  
Genetic Modifier ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Anomaly ◽  
Molecular Evidence ◽  
Single Nucleotide Variants ◽  
Experimental Proof ◽  
Phenotype Analysis ◽  
Oligogenic Inheritance ◽  
Induced Pluripotent

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant’s contribution as a genetic modifier.

Identification of Genetic Modifiers Associated with Risk of Stroke in Children with Sickle Cell Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3228-3228
Author(s):  
Jonathan Michael Flanagan ◽  
Heidi Linder ◽  
Vivien Sheehan ◽  
Thad A Howard ◽  
Banu Aygun ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Association Studies ◽  
Snp Markers ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Sibling Pairs ◽  
Synonymous Mutations

Abstract Abstract 3228 Introduction: Stroke is one of the most catastrophic acute complications of sickle cell anemia (SCA), occurring in 11% of patients before 20 years of age. A further 20 to 30% of children with SCA will develop less clinically overt cerebrovascular disease events such as transient ischemic attacks (TIA) and silent infarcts. There is a definite need for biomarkers that could determine the cause of these irreversible cerebrovascular events and which might predict children at greatest risk. Previous studies of sibling pairs have shown that there is a genetic component to cerebrovascular disease development but few genetic modifiers have been validated as having a substantial effect on risk of stroke. The aim of this study was to perform an unbiased whole genome search for genetic modifiers of stroke risk in SCA. Methods: Pediatric patients with SCA and documented primary stroke (n=177) were compared to a pediatric control non-stroke group with SCA (n=335). All control patients were over 5 years old and without previous clinical stroke prior to beginning any clinical treatment. Genome wide association studies (GWAS) were performed using genotype data obtained from Affymetrix SNP6.0 arrays. A pooled DNA approach was used to perform whole exome sequencing (WES) by Illumina next generation sequencing of pooled control (n=104) and pooled stroke (n=120) groups. Results: From the Affymetrix SNP6.0 GWAS data, 139 single nucleotide polymorphisms (SNP) were identified with stroke association. From the WES, 294 non-synonymous mutations were found to be significantly associated with stroke. In combination, 11 mutations identified by WES were located within 250kb of a SNP identified by GWAS (Table 1). These 11 mutations represent key areas of the genome that are targets for further in depth study. To next validate the genetic variants identified by WES with association with risk of stroke, 21 candidate mutations were genotyped in an independent cohort of control (n=231) and stroke (n=57) patients with SCA. One mutation in GOLGB1 (Y1212C) was corroborated as having significant association with lower risk of stroke (p=0.02). Conclusion: This mutation in GOLGB1 is predicted to effect the golgi associated function of the encoded protein and future studies will focus on how this functional mutation may protect against development of cerebrovascular disease in the context of SCA. For all variants with significant association with stroke, the chromosomal position of each variant identified by WES (n=300, p<0.001) was compared to the location of all SNP markers (n=139, p<0.0001). We identified 11 variants by WES where there was at least one SNP marker within 250kb. These variants all represent excellent regions of the genome for future study. The four variants highlighted with a asterisk (*) are variants predicted by PolyPhen2 or SIFT to be deleterious. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

2017 ◽  
Vol 114 (23) ◽  
pp. 6080-6085 ◽  
Author(s):  
Natassia M. Vieira ◽  
Janelle M. Spinazzola ◽  
Matthew S. Alexander ◽  
Yuri B. Moreira ◽  
Genri Kawahara ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Neuromuscular Diseases ◽  
Genetic Modifiers ◽  
Cardiorespiratory Failure ◽  
Transfer Protein ◽  
Phosphorylated Akt ◽  
Phosphatidylinositol Transfer Protein ◽  
Phosphatidylinositol Transfer ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these “escaper” dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.

Abstract 41: Dnajb6b Is A Novel Genetic Modifier For Cardiomyopathy That Regulates ER Stress Response

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yonghe Ding ◽  
Weibin Liu ◽  
Beninio Gore ◽  
Stephen C Ekker ◽  
Xiaolei Xu
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Insertional Mutagenesis ◽  
Genetic Modifier ◽  
Phenotypic Expression ◽  
Modifier Genes ◽  
Genetic Modifiers ◽  
Loss Of Function ◽  
Adult Zebrafish ◽  
Er Stress Response

Background: Cardiomyopathy and heart failure affect millions of people worldwide. Because genetic modifiers contribute in large part to the highly variable phenotypic expression of cardiomyopathy in patients even with identical disease-causing mutations, the identification of modifier genes for this disease will greatly improve risk stratification, prognostic test development, and personalized therapy. However, only a rather limited number of modifier genes for cardiomyopathy have been identified sporadically. Objective: To identify genetic modifiers for cardiomyopathy using a novel insertional mutagenesis screening approach in adult zebrafish. Methods and Results: We screened 476 gene break-transposon (GBT) lines and isolated 44 zebrafish insertional cardiac (ZIC) mutants. Employing doxorubicin (DOX) stress to these ZIC mutants, we identified four candidate GBT lines that modified the progression of DOX-induced cardiomyopathy. Here, we report the detailed study of the GBT0411 mutant that exacerbated DOX-induced cardiomyopathy. GBT0411 mutant was tagged to the dnajb6b gene. Mutations in the short (sarcomeric) isoform of its human homologue gene DNAJB6 was recently reported to cause limb-girdle muscular dystrophy type 1D. Interestingly, our data showed that long (nuclei) isoform (dnajb6b[L]) was the major isoform expressed in the heart, and loss-of-function of which deteriorated the progression of DOX-induced cardiomyopathy. We further found that a cardiomyocyte-specific dnajb6b(L) transgene reverted the deleterious modifying effect of GBT0411 mutant, and exerted a cardioprotective function on chronic anemia induced cardiomyopathy. Mechanistically, Dnajb6b(L) could partially localize to endoplasmic reticulum (ER) upon ER stress, and function as an ER stress suppressor. Indeed, inhibition of ER stress by using a chemical chaperon mimics the cardioprotective effect of dnajb6b(L) transgene. Conclusions: By conducting an unbiased mutagenesis screening in adult zebrafish, we identified dnajb6b as a novel genetic modifier for cardiomyopathy. A cardioprotective function was identified by overexpressing its long isoform in cardiomyocytes, which might be conveyed by inhibition of ER stress response.

scholarly journals PhenoModifier: a genetic modifier database for elucidating the genetic basis of human phenotypic variation

2019 ◽  
Author(s):  
Hong Sun ◽  
Yangfan Guo ◽  
Xiaoping Lan ◽  
Jia Jia ◽  
Xiaoshu Cai ◽  
...  
Keyword(s):  
Phenotypic Variation ◽  
Large Scale ◽  
Clinical Decision Making ◽  
Genetic Interaction ◽  
Genetic Modifier ◽  
Modifier Genes ◽  
Genetic Modifiers ◽  
Sequencing Data ◽  
Comprehensive Overview ◽  
Full Spectrum

Abstract From clinical observations to large-scale sequencing studies, the phenotypic impact of genetic modifiers is evident. To better understand the full spectrum of the genetic contribution to human disease, concerted efforts are needed to construct a useful modifier resource for interpreting the information from sequencing data. Here, we present the PhenoModifier (https://www.biosino.org/PhenoModifier), a manually curated database that provides a comprehensive overview of human genetic modifiers. By manually curating over ten thousand published articles, 3078 records of modifier information were entered into the current version of PhenoModifier, related to 288 different disorders, 2126 genetic modifier variants and 843 distinct modifier genes. To help users probe further into the mechanism of their interested modifier genes, we extended the yeast genetic interaction data and yeast quantitative trait loci to the human and we also integrated GWAS data into the PhenoModifier to assist users in evaluating all possible phenotypes associated with a modifier allele. As the first comprehensive resource of human genetic modifiers, PhenoModifier provides a more complete spectrum of genetic factors contributing to human phenotypic variation. The portal has a broad scientific and clinical scope, spanning activities relevant to variant interpretation for research purposes as well as clinical decision making.

scholarly journals Consistent Assignment of Risk and Benign Allele at rs2303153 in the CF Modifier Gene SCNN1B in Three Independent F508del-CFTR Homozygous Patient Populations

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1554
Author(s):  
Frauke Stanke ◽  
Tim Becker ◽  
Haide Susanne Ismer ◽  
Inga Dunsche ◽  
Silke Hedtfeld ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Risk Allele ◽  
Association Studies ◽  
Regulatory Element ◽  
Genetic Modifier ◽  
Modifier Gene ◽  
Intestinal Epithelia ◽  
Transepithelial Sodium Transport ◽  
Homozygous Patient

CFTR encodes for a chloride and bicarbonate channel expressed at the apical membrane of polarized epithelial cells. Transepithelial sodium transport mediated by the amiloride-sensitive sodium channel ENaC is thought to contribute to the manifestation of CF disease. Thus, ENaC is a therapeutic target in CF and a valid cystic fibrosis modifier gene. We have characterized SCNN1B as a genetic modifier in the three independent patient cohorts of F508del-CFTR homozygotes. We could identify a regulatory element at SCNN1B to the genomic segment rs168748-rs2303153-rs4968000 by fine-mapping (Pbest = 0.0177), consistently observing the risk allele rs2303153-C and the contrasting benign allele rs2303153-G in all three patient cohorts. Furthermore, our results show that expression levels of SCNN1B are associated with rs2303153 genotype in intestinal epithelia (P = 0.003). Our data confirm that the well-established biological role of SCNN1B can be recognized by an association study on informative endophenotypes in the rare disease cystic fibrosis and calls attention to reproducible results in association studies obtained from small, albeit carefully characterized patient populations.

scholarly journals A candidate genetic modifier and autosomal recessive cause of Brugada syndrome that may alter the circadian expression of SCN5A

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
L Seed ◽  
T Hearn
Keyword(s):  
Circadian Clock ◽  
Brugada Syndrome ◽  
Autosomal Recessive ◽  
Genetic Modifier ◽  
Cardiac Conduction ◽  
P Value ◽  
Functional Assay ◽  
Genetic Modifiers ◽  
Monogenic Diseases ◽  
Support Fund

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a generous grant from the Newnham College Senior Members Research Support fund. Introduction Inherited cardiac arrhythmias (ICAs) are a major cause of sudden cardiac death (SCD) in the young. ICAs are caused by variants in genes encoding ion channels that predispose individuals to life-threatening arrhythmic events. Early diagnosis to facilitate implementation of effective clinical interventions that greatly reduce SCD risk is critical. ICAs have traditionally been considered monogenic diseases. However, the genomic architecture of ICAs is likely a continuum, ranging from monogenic and near-monogenic (strong genetic factor influenced by a few genetic modifiers) to oligogenic (cumulative effects of coinheritance of many genetic modifiers). The circadian clock, which is predicted to control the expression of one third of the protein-coding genome, has been implicated in contributing to ICAs because the incidence of arrhythmic events in ICA patients oscillates with a period of 24 hours. We therefore hypothesised that it may contribute to oligogenic disease. Purpose To identify variants that may contribute to ICAs and that are located in cis-regulatory motifs that are both functionally predicted to be binding sites for clock transcription factors and located in the promoters of ICA-associated genes predicted to exhibit diurnal rhythmic expression. Methods Genes associated with ICAs and predicted to be rhythmically expressed were identified and the region 1kb upstream of their transcription start sites screened for mammalian circadian motifs. Whole genome sequencing data from participants with ICAs in The 100,000 Genomes Project was interrogated for variants within these motifs. Results Two variants in the SCN5A promoter were significantly associated with Brugada syndrome (BrS) (OR = 2.77, p-value &lt;2.2E-16; OR = 2.11, p-value = 6.23E-14). The variants were found in high linkage disequilibrium (D’=0.988, p-value &lt;2.2E-16). This 2-variant haplotype was enriched in BrS patients who did (OR = 2.43, p-value = 7.07E-08; OR = 1.32, p-value = 0.0204) and did not (OR = 3.00, p-value &lt;2.2E-16; OR = 1.78, p-value = 8.30E-09) have a likely genomic cause, implying that it may be a genetic modifier of BrS. This haplotype in the homozygous state was significantly enriched in individuals with BrS in whom a likely genomic cause had not been identified, suggesting it may be an autosomal recessive cause (OR = 0.102, Fisher’s p-value = 0.0120). Conclusion This haplotype has previously been reported to modulate BrS severity in a large family with a pathogenic SCN5A variant and has demonstrated a trend towards reduced SCN5A expression in murine cardiomyocytes – a molecular mechanism that slows cardiac conduction, predisposing individuals to BrS. Therefore, this 2-variant haplotype, or 1 variant therein, in the SCN5A promoter is a putative genetic modifier and autosomal recessive cause of BrS. Future work includes functional assay in human cardiomyocytes to characterise its molecular consequences on SCN5A expression and the circadian clock.

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