Identification of PRDM 16 as a Novel Gene for Cardiomyopathy and a Possible Therapeutic Target for Heart Failure

Introduction: Deletion 1p36 syndrome is the most common terminal deletion syndrome. The authors describe a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM).

Results: Using their own data and publically available data from array comparative genomic hybridization, the authors identified a minimal deletion for the cardiomyopathy associated with del1p36 that included only the terminal 13 exons of the transcription factor PRDM 16 (PR domain containing 16). Resequencing of PRDM 16 in a cohort of 75 nonyndromic patients with LVNC detected three sporadic de novo mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, the authors found five individuals with four previously unreported nonsynonymous variants in the coding region of PRDM 16. None of the PRDM 16 mutations identified were observed in over 6,500 controls. PRDM 16 has not previously been associated with cardiac disease. Modeling of PRDM 16 haploinsufficiency and a human truncation mutant in zebra fish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes, and also revealed evidence of impaired cardiomyocyte proliferative capacity. These observations can be completely rescued by the application of five structurally related compounds in the zebrafish.

Conclusion: In conclusion, mutations in the human PRDM 16 cause the cardiomyopathy in 1p36 deletion syndrome as well as a significant proportion of isolated LVNC and DCM. The rescue of the cardiac phenotype in the zebrafish might lead to a novel therapeutic target for heart failure.