Identification of PRDM16 as a disease gene for left ventricular non-compaction and the efficient generation of a personalized disease model in zebrafish. A.-K. Arndt1,2, S. Schaefer3, R. Siebert4, S. A. Cook5, H.-H. Kramer2, S. Klaassen6, C. A. MacRae1 1) Cardiovascular Division, Brigham and Women's Hospital, Boston, MA; 2) Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany,; 3) Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; 4) Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany; 5) National Heart Centre, Singapore; 6) Department of Pediatric Cardiology, Charité, Berlin, Germany.

   Using our own data and publically available array comparative genomic hybridization data, we identified the transcription factor PRDM16 (PR domain containing 16) as a causal gene for the cardiomyopathy associated with monosomy 1p36, and confirmed its role in individuals with non-syndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). In a cohort of 75 non-syndromic patients with LVNC we detected 3 sporadic mutations, including 1 truncation mutant, 1 frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported non-synonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in over 6500 controls. PRDM16 has not previously been associated with cardiovascular disease. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in impaired cardiomyocyte proliferation with associated physiologic defects in cardiac contractility and cell-cell coupling. Using a phenotype-driven screening approach in the fish, we have identified 5 compounds that are able to rescue the physiologic defects associated with mutant or haploinsufficient PRDM16. Notably, all of the compounds had the capacity to restore cardiomyocyte proliferation and to prevent apoptosis in the model. Wildtype zebrafish also demonstrated a significant increase in cardiomyocyte numbers after treatment with the compounds suggesting a pro-proliferative effect of the compounds. In addition, the compounds also rescued the contractile and electrical defects observed in these disease models. These findings underline the importance of personalized disease models for specific pathways, to accelerate the exploration of disease biology and the development of innovative therapeutic approaches.

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