Year: 2016
Type: article
Abstract: OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM.
Authors: Rene L. Begay, Charles A. Tharp, August Martin, Sharon L. Graw, Gianfranco Sinagra, Daniela Miani, Mary E. Sweet, Dobromir B. Slavov, Neil Stafford, Molly J. Zeller, Rasha Alnefaie, Teisha J. Rowland, Francesca Brun, Kenneth L. Jones, Katherine Gowan, Luisa Mestroni, Deborah M. Garrity, Matthew R.G. Taylor
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,750
Awards: G1210576399, G1825981810, Whole genome DNA sequencing to identify novel genes in dilated cardiomyopathy, G252781271, G2594075514, G2899602109, G319511802, Genetics, Mechanisms and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy, G3665166657, G3793127575, G3876424838, G4102444154, G4146012505, G422257384, G4531593092, G4921130661, Molecular Genetics, Pathogenesis and Protein-Replacement Therapy in Arrhythmogenic Cardiomyopathy, Cardiomyocyte phenotype and mechanotransduction in Filamin C gene variants causing arrhythmogenic cardiomyopathy, G5639945339, Colorado Clinical and Translational Sciences Institute, G6300707817, G70312321, Familial Dilated Cardiomyopathy:Genetic Characterization, G741968312, G7466124990, Molecular Epidemiology of Dilated Cardiomyopath, Colorado Clinical and Translational Science Institute (UL1)
OpenAlex ID: W2477171588