Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.
Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.
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DOI：
10.1186/1471-2350-13-21
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发表时间：
2012-03-29
影响因子：
--
通讯作者：
Ahmad F
中科院分区：
文献类型：
--
作者：
Rajkumar R;Sembrat JC;McDonough B;Seidman CE;Ahmad F
编码核膜蛋白的TMEM43中的Ser358Leu突变与心律失常性右室心肌病（ARVC）有关。这种突变的发病机制尚不清楚。为了确定TMEM43突变作为ARVC病因的频率，我们筛选了11个ARVC家族的TMEM43突变和5个先前与该疾病有关的桥粒体基因。在转染野生型、突变型和1:2野生型：突变型TMEM43的COS-7细胞中进行功能研究，以确定Ser358Leu突变对TMEM43和其他核膜和桥粒体蛋白的稳定性和细胞定位的影响，通过溶解度测定和免疫荧光成像进行评估。评估可能受核层功能障碍影响的基因的mRNA表达。在先前记录的桥粒基因中发现了三个新的突变，但在TMEM43中没有突变。转染突变体TMEM43的COS-7细胞的桥粒稳定性没有变化。突变体TMEM43的稳定性和核膜定位正常，层粘连蛋白B和emerin也正常。突变体TMEM43没有改变位于13号染色体上的基因的表达，这些基因先前与导致骨骼肌营养不良的核膜蛋白突变有关。突变体TMEM43表现出正常的细胞定位，不破坏其他核膜和桥粒体蛋白的完整性和定位。TMEM43突变在ARVC中的致病作用尚不清楚。
The Ser358Leu mutation in TMEM43, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). The pathogenetic mechanisms of this mutation are poorly understood. To determine the frequency of TMEM43 mutations as a cause of ARVC, we screened 11 ARVC families for mutations in TMEM43 and five desmosomal genes previously implicated in the disease. Functional studies were performed in COS-7 cells transfected with wildtype, mutant, and 1:2 wildtype:mutant TMEM43 to determine the effect of the Ser358Leu mutation on the stability and cellular localization of TMEM43 and other nuclear envelope and desmosomal proteins, assessed by solubility assays and immunofluorescence imaging. mRNA expression was assessed of genes potentially affected by dysfunction of the nuclear lamina. Three novel mutations in previously documented desmosomal genes, but no mutations in TMEM43, were identified. COS-7 cells transfected with mutant TMEM43 exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant TMEM43 did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies. Mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of TMEM43 mutations in ARVC remains uncertain.
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影响因子：
--
作者：
Beffagna G;De Bortoli M;Nava A;Salamon M;Lorenzon A;Zaccolo M;Mancuso L;Sigalotti L;Bauce B;Occhi G;Basso C;Lanfranchi G;Towbin JA;Thiene G;Danieli GA;Rampazzo A
通讯作者：
Rampazzo A
影响因子：
--
作者：
Bhuiyan, Zahurul A.;Jongbloed, Jan D. H.;van Tintelen, J. Peter
通讯作者：
van Tintelen, J. Peter
DOI：
10.1152/ajpheart.00254.2009
发表时间：
2010-04-01
影响因子：
4.8
作者：
Rajkumar, Revathi;Konishi, Kazuhisa;Ahmad, Ferhaan
通讯作者：
Ahmad, Ferhaan
影响因子：
5.5
作者：
Bauce, Barbara;Nava, Andrea;Rampazzo, Alessandra
通讯作者：
Rampazzo, Alessandra
影响因子：
24
作者：
Xu, Tianhong;Yang, Zhao;Vatta, Matteo;Rampazzo, Alessandra;Beffagna, Giorgia;Pillichou, Kalliopi;Scherer, Steven E.;Saffitz, Jeffrey;Kravitz, Joshua;Zareba, Wojciech;Danieli, Gian Antonio;Lorenzon, Alessandra;Nava, Andrea;Bauce, Barbara;Thiene, Gaetano;Basso, Cristina;Calkins, Hugh;Gear, Kathy;Marcus, Frank;Towbin, Jeffrey A.
通讯作者：
Towbin, Jeffrey A.