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Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy

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  • Anne-Karin Arndt
  • Sebastian Schafer
  • Jorg-Detlef Drenckhahn
  • M Khaled Sabeh
  • Eva R Plovie
  • Almuth Caliebe
  • Eva Klopocki
  • Gabriel Musso
  • Andreas A Werdich
  • Hermann Kalwa
  • Matthias Heinig
  • Robert F Padera
  • Katharina Wassilew
  • Julia Bluhm
  • Christine Harnack
  • Janine Martitz
  • Paul J Barton
  • Matthias Greutmann
  • Felix Berger
  • Norbert Hubner
  • Reiner Siebert
  • Hans-Heiner Kramer
  • Stuart A Cook
  • Calum A MacRae
  • Sabine Klaassen
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Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome 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 nonsyndromic individuals with LVNC detected three 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, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 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 nonsyndromic LVNC and DCM.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume93
Issue number1
Pages (from-to)67-77
Number of pages11
ISSN0002-9297
DOIs
Publication statusPublished - 11 Jul 2013
Externally publishedYes

    Research areas

  • Animals, Cardiomyopathy, Dilated, Case-Control Studies, Cell Proliferation, Chromosome Deletion, Chromosome Disorders, Chromosome Mapping, Chromosomes, Human, Pair 1, Comparative Genomic Hybridization, DNA-Binding Proteins, Exons, Frameshift Mutation, Humans, Isolated Noncompaction of the Ventricular Myocardium, Mutation, Missense, Myocardial Contraction, Myocytes, Cardiac, Transcription Factors, Zebrafish, Journal Article, Research Support, Non-U.S. Gov't

ID: 49734442