title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Anne-Karin
authors.initials: AK
authors.lastname: Arndt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.forename: Jorg-Detlef
authors.initials: JD
authors.lastname: Drenckhahn
authors.forename: M Khaled
authors.initials: MK
authors.lastname: Sabeh
authors.forename: Eva R
authors.initials: ER
authors.lastname: Plovie
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Gabriel
authors.initials: G
authors.lastname: Musso
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Werdich
authors.forename: Hermann
authors.initials: H
authors.lastname: Kalwa
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Katharina
authors.initials: K
authors.lastname: Wassilew
authors.forename: Julia
authors.initials: J
authors.lastname: Bluhm
authors.forename: Christine
authors.initials: C
authors.lastname: Harnack
authors.forename: Janine
authors.initials: J
authors.lastname: Martitz
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Barton
authors.forename: Matthias
authors.initials: M
authors.lastname: Greutmann
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Hans-Heiner
authors.initials: HH
authors.lastname: Kramer
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000235:genetics*; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; D014157:Transcription Factors