Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.
Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.
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分子遗传和功能表征暗示肌肉限制的卷曲圈基因（MURC）是家族性扩张性心肌病的因果基因。
DOI：
10.1161/circgenetics.111.959866
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发表时间：
2011-08-01
期刊：
影响因子：
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通讯作者：
Marian AJ
中科院分区：
文献类型：
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作者：
Rodriguez G;Ueyama T;Ogata T;Czernuszewicz G;Tan Y;Dorn GW 2nd;Bogaev R;Amano K;Oh H;Matsubara H;Willerson JT;Marian AJ
扩张型心肌病（DCM）和肥厚型心肌病（HCM）分别是收缩性和舒张性心力衰竭的经典形式。编码肌节和细胞骨架蛋白的基因突变是HCM和DCM的主要原因。MURC，编码肌肉限制性卷曲螺旋，一种Z线蛋白，调节小鼠的心脏功能。我们研究了MURC在人类心肌病中的潜在因果作用。我们对1,199名个体进行了MURC测序，其中包括383名DCM先证者，307名HCM先证者和509名健康对照者。我们在8个无关先证者中发现了6个杂合DCM特异性错义变异体（p.N128K、p.R140W、p.L153P、p.S307T、p.P324L和p.S364L）。在小家系中，p.N128K和p.S307T与DCM的遗传分离（χ2=8.5，p=0.003）。认为变异体p.N128K、p.R140W、p.L153P和p.S364L可能或可能具有损害性。变异p.P324L在三个独立的先证者中复发，包括一个具有TPM 1突变（p.M245T）的先证者。在3例HCM先证者中发现一种缺失型（p.L232-R238 del），但在1例MYH 7突变（p.L970V）的HCM家系中未发现这种缺失型。突变携带者的表型值得注意的是进行性心力衰竭，导致心脏移植的四名患者，传导缺陷和房性心律失常。与野生型MURC相比，用重组腺病毒转导的新生大鼠心肌细胞中突变型MURC蛋白的表达与RhoA活性降低、肥大标志物的mRNA水平降低和心肌细胞大小减小相关。MURC突变对MURC功能产生功能丧失效应，可能是人DCM的致病变异。HCM中缺失突变的因果作用尚不确定。
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. We sequenced MURC in 1,199 individuals including 383 probands with DCM, 307 with HCM and 509 healthy controls. We found six heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L and p.S364L) in eight unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ2=8.5, p=0.003). Variants p.N128K, p.R140W, p.L153P and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in three independent probands, including one proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in three unrelated HCM probands but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L970V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in four patients, conduction defects and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared to wild type MURC. MURC mutations impart loss-of-function effects on MURC functions and are likely causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.