This proposal addresses the molecular epidemiology of dilated cardiomyopathy by determining the frequency of disease gene mutations, and the genotype/phenotype correlations in the patient population, and their clinical relevance. Idiopathic dilated cardiomyopathy (DCM) is a disease affecting the cardiac muscle and is a primary cause of heart failure leading to heart transplant. The etiology of DCM is mainly unknown, but the disease is frequently inherited and genetically heterogeneous. Linkage studies have identified 17 FDC disease loci including a locus mapped by the P.I.'s laboratory on chromosome 9 in a large kindred with autosomal dominant FDC. Thus far, 8 disease genes have been identified: the P.I.'s laboratory has contributed to the discovery of mutations in dystrophin gene leading to X-linked FDC, and more recently, has discovered lamin A/C gene mutations in patients with FDC and variable skeletal muscle involvement. Other investigators have reported mutations in cardiac actin, delta-sarcoglycan, desmin, tafazzin, beta-myosin heavy chain and troponin T leading to FDC. However, the prevalence, type and clinical relevance of cytoskeletal gene mutations in FDC, and in the overall DCM population are unknown. This application proposes a series of experiments designed to test the following hypotheses: 1) gene mutations are a frequent cause of FDC, 2) different gene mutations may have different frequency, different prognostic value, and different clinical relevance, 3) several FDC genes are still unidentified, and they are likely to encode cytoskeletal proteins.
The Specific Aims of this proposal are: 1) to investigate of a cohort of patients with FDC and to evaluate their relatives to determine the inheritance pattern, the phenotype, the natural history, and recruit for molecular genetics studies; 2) to identify and characterize novel genes causing FDC using a candidate gene approach and a positional candidate cloning approach; 3) to analyze the molecular epidemiology of known and novel disease genes by studying the prevalence, type, and genotype/phenotype correlation of the FDC gene mutations in a large patient population with or without a familial trait. Clinical data, DNA and, in the case of FDC, lymphoblastoid cell lines have already been collected from 478 subjects, and we anticipate the enrollment of 20 to 30 new families/year. The experimental methods include mutation screening of known and novel candidate genes, positional cloning of the FDC gene on chromosome 9 by linkage and association studies, analysis of the frequency and genotype/phenotype correlations using a large database designed for these studies. The identification of the genes and mutations responsible for DCM will greatly increase the understanding of the molecular basis of this disease and will allow for the development of new molecular- based diagnostic and therapeutic strategies.
| Sweet, Mary E; Cocciolo, Andrea; Slavov, Dobromir et al. (2018) Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure. BMC Genomics 19:812 |
| Peña, Brisa; Laughter, Melissa; Jett, Susan et al. (2018) Injectable Hydrogels for Cardiac Tissue Engineering. Macromol Biosci 18:e1800079 |
| McNally, Elizabeth M; Mestroni, Luisa (2017) Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. Circ Res 121:731-748 |
| Dal Ferro, Matteo; Stolfo, Davide; Altinier, Alessandro et al. (2017) Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. Heart 103:1704-1710 |
| Te Riele, Anneline S J M; Agullo-Pascual, Esperanza; James, Cynthia A et al. (2017) Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res 113:102-111 |
| Brun, Francesca; Groeneweg, Judith A; Gear, Kathleen et al. (2016) Risk Stratification in Arrhythmic Right Ventricular Cardiomyopathy Without Implantable Cardioverter-Defibrillators. JACC Clin Electrophysiol 2:558-564 |
| Porto, Andrea Giuseppe; Brun, Francesca; Severini, Giovanni Maria et al. (2016) Clinical Spectrum of PRKAG2 Syndrome. Circ Arrhythm Electrophysiol 9:e003121 |
| Rowland, Teisha J; Graw, Sharon L; Sweet, Mary E et al. (2016) Obscurin Variants in Patients With Left Ventricular Noncompaction. J Am Coll Cardiol 68:2237-2238 |
| Begay, Rene L; Tharp, Charles A; Martin, August et al. (2016) FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy. JACC Basic Transl Sci 1:344-359 |
| Sbaizero, O; DelFavero, G; Martinelli, V et al. (2015) Analysis of long- and short-range contribution to adhesion work in cardiac fibroblasts: an atomic force microscopy study. Mater Sci Eng C Mater Biol Appl 49:217-224 |
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