JBC：高达8%的南亚人群携带心力衰竭风险基因突变

  近日，一项芝加哥大学研究人员的最新研究结果显示，在印度、巴基斯坦等其它南亚国家中有高达8%的个体都携带有一种可引发心衰及致死性心脏病的基因突变，相关研究刊登于国际杂志Journal of Biological Chemistry上。

  该研究揭示了这一基因突变如何损伤个体心脏泵血的能力，研究结果或为开发预防及治疗易感个体的新型疗法提供帮助，研究者表示，据估计世界上大约有5500万南亚人群都携带有这种基因突变，而其中在美国有20万人都携带有这种潜在致死性突变。

  这种基因突变会引发肥厚性心肌病，肥厚性心肌病是遗传性心脏病的一种常见形式，而且其也是引发年轻人心脏猝死的主要原因。此前研究者们发现大约有5%至8%的个体会携带这种基因突变，而80%携带该基因突变的个体可能会在其45岁以后患上心衰。早在2001年，研究者就在国际心脏研究学会世界会议上首次报道了这种遗传突变，这种突变很有可能在3.3万年至5.5万年前在单一个体中发生，随后便扩散到了南亚地区。

  这种突变基因可以编码一种名为心脏肌凝蛋白结合蛋白-C（cMyBP-C）的蛋白质，该蛋白质可以控制心肌收缩，对于维持心脏的正常功能非常关键；在突变的基因中发生了25个碱基对的缺失，导致的结果就是蛋白质的尾部结构发生了改变。研究者Sadayappan说道，本研究中我们在培养皿中将突变基因引入到了成年大鼠的心肌细胞中，同时以引入正常基因的心肌细胞进行对比研究。

  在突变基因的细胞中，cMyBP-C蛋白并不会参与形成肌节，肌节是心脏肌肉的基本构成单元；因此突变的基因并不会帮助形成肌节，而该研究也首次揭示了突变蛋白表达对于引发心功能障碍非常关键。研究结果或可帮助开发潜在的疗法来从患者机体中移除突变蛋白，从而引入正常的cMyBP-C蛋白；研究人员希望后期可以在那些携带突变基因的个体中鉴别出可以加重肥厚性心肌病的风险因子。（转化医学网360zhyx.com）

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转化医学网推荐的原文摘要：

A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction
Journal of Biological Chemistry doi: 10.1074/jbc.M114.607911
Diederik W. D. Kuster1, Suresh Govindan1, Tzvia I. Springer2, Jody L. Martin1, Natosha L. Finley2 and Sakthivel Sadayappan1*
Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often, MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-basepair deletion in MYBPC3 is inherited in millions worldwide. While this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-CC10mut), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-CC10mut in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca2+-transients, compared to wild-type cMyBP-C expression (cMyBP-CWT) and controls. Forty-eight hours after infection, 44% of cMyBP-CWT and 36% of cMyBP-CC10mut protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little, or no, localization of cMyBP-CC10mut to the C-zone, while cMyBP-CWT mostly showed C-zone staining, suggesting that cMyBP-CC10mut could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-CC10mut resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-CC10mut displayed significantly reduced fractional shortening, sarcomere shortening and relaxation velocities, apparently caused by defects in sarcomere function, as Ca2+-transients were unaffected. Co-sedimentation and protein crosslinking assays confirmed that C10mut causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-CC10mut, providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-CC10mut protein is sufficient to cause contractile dysfunction in vitro.