Structural analysis of obscurin gene in hypertrophic cardiomyopathy
Structural analysis of obscurin gene in hypertrophic cardiomyopathy
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DOI：
10.1016/j.bbrc.2007.07.183
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发表时间：
2007-10-19
影响因子：
3.1
通讯作者：
Kimura, Akinorl
中科院分区：
文献类型：
--
作者：
Arimura, Takuro;Matsumoto, Yuji;Kimura, Akinorl
肥厚型心肌病（HCM）是一种以左室肥厚伴舒张功能障碍为特征的心脏病。分子遗传学研究表明，HCM是由肌节/Z带组分（包括肌联蛋白/连接蛋白及其相关蛋白）的基因突变引起的。然而，在大约一半的患者中可以发现致病突变，这表明其他致病基因仍有待确定。为了探索一种新的疾病基因，我们在HCM患者中寻找obscurin基因（OBSCN）突变，因为obscurin与titin/connectin相互作用。在一名患者中发现了两个连锁变体Arg 4344 Gln和Ala 4484 Thr，功能分析表明Arg 4344 Gln影响obscurin与titin/connectin的Z9-Z10结构域的结合，而Ala 4484 Thr则不影响。Myc标记的obscurin显示Arg 4344 GIn损害obscurin在Z带的定位。这些结果表明，obscurin异常可能参与HCM的发病机制。(C)2007年爱思唯尔公司All rights reserved.
Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by left ventricular hypertrophy with diastolic dysfunction. Molecular genetic studies have revealed that HCM is caused by mutations in genes for sarcomere/Z-band components including titin/connectin and its associate proteins. However, disease-causing mutations can be found in about half of the patients, suggesting that other disease-causing genes remain to be identified. To explore a novel disease gene, we searched for obscurin gene (OBSCN) mutations in HCM patients, because obscurin interacts with titin/connectin. Two linked variants, Arg4344GIn and Ala4484Thr, were identified in a patient and functional analyses demonstrated that Arg4344Gln affected binding of obscurin to Z9-Z10 domains of titin/connectin, whereas Ala4484Thr did not. Myc-tagged obscurin showed that Arg4344GIn impaired obscurin localization to Z-band. These observations suggest that the obscurin abnormality may be involved in the pathogenesis of HCM. (C) 2007 Elsevier Inc. All rights reserved.