1p36 Deletion Syndrome, PRDM16 in Heart Failure
1p36 deletion syndrome is recognized as the most terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyophathy associated with monosomy 1p36, and confirm its role in non-syndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). Using our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with del1p36 that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 non-syndromic individuals with LVNC detected 3 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 6400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes, and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of non-syndromic LVNC and DCM.
Fig 1. LVNC, Echocardiography in Diastole
Fig 2. LVNC, Echocardiography in Systole
Fig 3. Mutations reside within the genomic sequence of exon 9 of PRDM16 in patients with LVNC
Fig 4. PRDM16 expression in the left ventricle of wild-type mice and human heart. In adult human heart PRDM16 is expressed in the nuclei of both cardiomyocytes and interstitial cells (Fig. 4a). At mouse embryonic day (E) 13.5 (Fig. 4b), PRDM16 protein was expressed throughout the left ventricle but was most prominent in the endocardial and epicardial layers. In the adult mouse (Fig. 4c) PRDM16 expression was somewhat reduced overall compared to the embryonic heart but was still predominantly localized to the nuclei of cardiomyocytes. Taken together, these data support the hypothesis that PRDM16 is present and functional as a transcription factor in the nuclei of cardiomyocytes in the embryonic and adult mammalian left ventricular myocardium.