Vasile Vlad C, Ommen Steve R, Edwards William D, Ackerman Michael J
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Biochem Biophys Res Commun. 2006 Jul 7;345(3):998-1003. doi: 10.1016/j.bbrc.2006.04.151. Epub 2006 May 4.
The R975W mutation, in the alternatively spliced exon 19 of vinculin (VCL) which yields the isoform metavinculin, was associated previously with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and shown to alter in vivo organization of intercalated discs. We tested the hypothesis that alterations in the ubiquitously expressed, VCL-encoded protein, vinculin, may provide a pathogenic substrate for HCM. Comprehensive mutational analysis of VCL's 22 translated exons was performed in a cohort of 228 unrelated patients with genotype negative HCM, having no identifiable mutations in 12 HCM-associated myofilament/Z-disc-encoding genes. A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy. This mutation was not detected in 400 reference alleles. Immunohistochemical analysis of the proband's myectomy specimen demonstrated markedly reduced vinculin levels in the intercalated discs. We provide the first report of a cardiomyopathy associated mutation in vinculin. Despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype.
纽蛋白（VCL）的选择性剪接外显子19中的R975W突变可产生亚型间线蛋白，该突变先前与肥厚型心肌病（HCM）和扩张型心肌病（DCM）相关，并显示会改变闰盘的体内组织结构。我们检验了以下假设：普遍表达的VCL编码蛋白纽蛋白的改变可能为HCM提供致病基础。对228名无亲缘关系的基因型阴性HCM患者进行了VCL的22个翻译外显子的全面突变分析，这些患者在12个与HCM相关的肌丝/ Z盘编码基因中未发现可识别的突变。在一名患有严重梗阻性、心室中部肥厚的患者中鉴定出一种涉及保守残基的新型错义突变L277M-VCL。在400个参考等位基因中未检测到该突变。对先证者心肌切除标本的免疫组织化学分析显示，闰盘中纽蛋白水平明显降低。我们首次报道了纽蛋白中与心肌病相关的突变。尽管纽蛋白普遍表达，但与HCM相关的VCL突变在临床上产生了心脏特异性表型。
