Beyond the sarcomere:: CSRP3 mutations cause hypertrophic cardiomyopathy
Beyond the sarcomere:: CSRP3 mutations cause hypertrophic cardiomyopathy
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DOI：
10.1093/hmg/ddn160
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发表时间：
2008-09-15
影响因子：
3.5
通讯作者：
Oezcelik, Cemil
中科院分区：
文献类型：
--
作者：
Geier, Christian;Gehmlich, Katja;Oezcelik, Cemil
肥厚型心肌病（HCM）是一种常见的遗传性心脏病，也是年轻人心源性猝死的最常见原因。目前已知的大多数 HCM 疾病基因都编码肌节蛋白。先前的研究已表明 CSRP3 错义突变与扩张型心肌病 (DCM) 或 HCM 之间存在关联，但所有这些研究均无法为 CSRP3 突变的致病作用提供全面的遗传证据。我们使用连锁分析，在一个受 HCM 影响的德国大家庭中发现了 CSRP3 错义突变。我们确认 CSRP3 是 HCM 疾病基因。此外，在其他四个家族中还发现了与 HCM 分离的 CSRP3 错义突变。我们使用新设计的单克隆抗体来证明肌肉 LIM 蛋白 (MLP)（CSRP3 编码的蛋白质）主要是心肌细胞的胞质成分，并不紧密锚定于肌节结构。我们来自体外和体内分析的功能数据表明，在携带 CSRP3 错义突变的 HCM 患者的心脏中，至少一种 MLP 突变形式似乎不稳定。我们还提供了受影响者患有轻度骨骼肌疾病的证据。我们的结果支持 HCM 不仅仅是一种肌节疾病的观点，并且还表明受损的机械感觉应激信号可能与 HCM 的发病机制有关。
Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.