Combinatorial interactions of genetic variants in human cardiomyopathy
Autor: | Kevin Tenerelli, Robert S. Ross, Chao Chen, Kirk L. Peterson, Nicholas J. Schork, Elie Farah, Ana Maria Manso, Ju Chen, Adam J. Engler, Qian Peng, Nancy D. Dalton, Dekker C. Deacon, Yusu Gu, Neil Tedeschi, Eric Adler, Ting Li, Vivien D. Tran, Neil C. Chi, Cassandra L. Happe |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Genetics Biomedical Engineering Medicine (miscellaneous) Bioengineering TPM1 Heritability Biology musculoskeletal system Penetrance Computer Science Applications 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Genetic variation cardiovascular system CRISPR cardiovascular diseases Expressivity (genetics) Allele Gene 030217 neurology & neurosurgery Biotechnology |
Zdroj: | Nature Biomedical Engineering. 3:147-157 |
ISSN: | 2157-846X |
Popis: | Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors. |
Databáze: | OpenAIRE |
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