Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy
Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy
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DOI：
10.1016/j.ajhg.2013.05.015
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Klaassen, Sabine
中科院分区：
文献类型：
--
作者：
Arndt, Anne-Karin;Schafer, Sebastian;Klaassen, Sabine
缺失1p36综合征是公认的最常见的终端缺失综合征。在这里，我们描述了与单体1p36相关的心肌病相关的缺失基因的缺失，并证实了其在非综合征性左室非压实性心肌病（LVNC）和扩张性心肌病（DCM）中的作用。利用我们自己的数据和来自阵列比较基因组杂交（aCGH）的公开数据，我们发现了与1p36del综合征相关的心肌病的最小缺失，仅包括转录因子PRDM16 （PR结构域包含16）的末端14外显子，该基因先前已被证明指导棕色脂肪的测定和分化。对75名LVNC非综合征个体的PRDM16进行重测序，检测到3个突变，包括一个截断突变，一个移码无效突变和一个错义突变。此外，在131例DCM患者的一系列心脏活检中，我们发现5例患者在PRDM16编码区有4个以前未报道的非同义变体。在6400多名对照中未观察到PRDM16突变。PRDM16先前并未与心脏病相关，但在小鼠和人类的整个发育过程中以及成人心脏中都存在于心肌细胞核中。在斑马鱼中建立PRDM16单倍不全和人类截断突变体的模型，导致心肌细胞的收缩功能障碍和部分解偶联，并显示心肌细胞增殖能力受损的证据。综上所述，PRDM16突变导致1p36缺失综合征心肌病以及一定比例的非综合征性LVNC和DCM。
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.