Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.
Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.
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DOI：
10.1371/journal.pone.0121723
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Favale S
中科院分区：
文献类型：
--
作者：
Forleo C;Carmosino M;Resta N;Rampazzo A;Valecce R;Sorrentino S;Iacoviello M;Pisani F;Procino G;Gerbino A;Scardapane A;Simone C;Calore M;Torretta S;Svelto M;Favale S
核纤层蛋白A/C基因（LMNA）的突变与扩张型心肌病（DCM）相关，最近又与严重的致瘤性右心室心肌病（ARVC）相关。观察到DCM和ARVC之间的遗传和表型重叠;导致由LMNA突变引起的心脏表型的分子病理机制尚未完全阐明。这项研究涉及一个大型意大利家族，跨越4代，具有不同表型的致心律失常性心肌病，包括ARVC、DCM、系统传导缺陷、室性心律失常和心源性猝死。对LMNA和ARVC相关基因PKP 2、DSP、DSG 2、DSC 2、JUP和CTNNA 3进行突变筛选。我们发现了一种新的杂合突变（c.418_438dup）在LMNA基因外显子2，发生在一个高度保守的蛋白质结构域在几个物种。这种新发现的变异在250名种族匹配的对照受试者中没有发现。基因型-表型相关性研究表明，LMNA突变与疾病表型共分离，并存在不完全和年龄相关的突变。根据临床、系谱和分子遗传学数据，认为这种突变可能是致病的。为了阐明其潜在的病理生理学影响，在表达EGFP标记的野生型和突变的LMNA构建体的培养的心肌细胞中进行该LMNA突变体的功能表征，并且表明增加的核膜脆性，导致应激诱导的细胞凋亡作为主要的发病机制。这项研究进一步扩展了LMNA基因在心脏纤层蛋白病发病机制中的作用，表明LMNA应包括在疑似致心律失常性心肌病患者的突变筛查中，特别是当他们有传导缺陷的心电图证据时。临床、遗传和功能数据的结合有助于深入了解这种危及生命的致瘤性心脏纤层病的发病机制。
Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.
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影响因子：
11.4
作者：
Marinho HS;Real C;Cyrne L;Soares H;Antunes F
通讯作者：
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影响因子：
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作者：
Nerheim, Pamela;Krishnan, Subramaniam C.;Shivkumar, Kalyanam
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Shivkumar, Kalyanam
DOI：
10.1016/s0735-1097(02)01724-2
发表时间：
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作者：
Arbustini, E;Pilotto, A;Tavazzi, L
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影响因子：
10.8
作者：
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通讯作者：
Delmar, Mario
DOI：
10.1186/1532-429x-13-30
发表时间：
2011-06-20
期刊：
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
影响因子：
--
作者：
Holmström M;Kivistö S;Heliö T;Jurkko R;Kaartinen M;Antila M;Reissell E;Kuusisto J;Kärkkäinen S;Peuhkurinen K;Koikkalainen J;Lötjönen J;Lauerma K
通讯作者：
Lauerma K