Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy
Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy
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DOI：
10.1093/cvr/cvm015
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发表时间：
2008-01-01
影响因子：
10.8
通讯作者：
Villard, Eric
中科院分区：
文献类型：
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作者：
Duboscq-Bidot, Laetitia;Xu, Peng;Villard, Eric
目的特发性扩张型心肌病(DCM)是一种以左室扩张和收缩功能受损为特征的心脏疾病。它是心力衰竭和心脏移植的主要原因。扩张型心肌病有类似于30%的病例是遗传起源的，并且与许多疾病基因的鉴定具有遗传异质性。然而，许多新的疾病基因仍有待发现。方法和结果对65例家族性和49例散发的扩张型心肌病患者进行了编码肌节蛋白myopalladin(MYPN，OMIM 608517)的基因序列测定和功能分析。我们在两个家系(R1088H和183fsX105)和两个散发病例(V1195M，P1112L)中发现了四个独立的杂合子突变。对于这三个错义突变，替代氨基酸在物种间是保守的。在400名对照组受试者中，所有突变均为缺失。携带R1088H突变的先证者的心脏组织的特异性免疫标记显示，Myopalladin在左室肌原纤维的Z带区域的定位减少。分析基因突变对新生大鼠心肌细胞的影响，发现V1195M和P1112L在心肌细胞中的表达与肌节结构紊乱和细胞过早死亡有关。对一例携带183fsX105突变的患者进行的基因特异性表达分析显示，突变的转录本缺失，提示为单倍体缺陷机制。结论基于遗传学、组织学和功能证据，我们在一个欧洲血统的人群中发现了一个与DCM相关的新基因，并观察到3-4%的病例发生突变。
Aims Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized by left ventricular dilatation and impaired systolic contraction. It is a major cause of heart failure and heart transplantation. DCM is of genetic origin in similar to 30% of cases and genetically heterogeneous with the identification of numerous disease genes. However, many new disease genes remain to be discovered. Focusing on gene products located in the sarcomere of cardiomyocytes as disease-causing candidates, we screened the gene encoding the sarcomeric Z-band protein myopalladin (MYPN, OMIM 608517) for mutation.Methods and results We sequenced the coding region in 114 (65 familial and 49 sporadic cases) independent DCM patients' DNA and functionally analysed the identified mutations. We identified four independent heterozygous mutations in two families (R1088H and 183fsX105) and two sporadic cases (V1195M, P1112L). For the three missense mutations, the substituted amino acids were conserved among species. All mutations were absent from 400 control subjects. Specific immunolabelling of heart tissue from a proband carrying the R1088H mutation showed a decreased localization of myopalladin at the Z-band area of left ventricular cardiac myofibrils. Analysis of the effects of the mutations after transfection in rat neonate cardiomyocytes indicated sarcomere disorganization and premature cell death associated with the V1195M and P1112L myopalladin expression. Allele-specific expression analysis of mRNA from a patient harbouring the 183fsX105 mutation indicated the absence of the mutated transcript, suggesting a haploinsufficiency mechanism.Conclusion Based on genetic, histological, and functional evidence, we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent.