A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions.
A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions.
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DOI：
10.1016/j.hrthm.2011.01.010
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发表时间：
2011-05
期刊：
影响因子：
5.5
通讯作者：
McKenna, William J.
中科院分区：
文献类型：
--
作者：
Gehmlich, Katja;Lambiase, Pier D.;Asimaki, Angeliki;Ciaccio, Edward J.;Ehler, Elisabeth;Syrris, Petros;Saffitz, Jeffrey E.;McKenna, William J.
关键词：
由心脏桥粒介导的细胞粘附是心肌间隙连接介导的适当电传播的先决条件。然而，这种相互依赖性背后的分子原理尚未完全理解。本研究的目的是确定一名临界诊断为致心律失常性右心室心肌病的患者右心室传导异常的潜在原因。为了评估分子变化，分析患者心肌组织的桥粒和间隙连接（连接蛋白43）蛋白水平和定位的改变。进行体外功能研究以表征桥粒突变的后果。斑珠蛋白信号的丢失在细胞连接处是明显的，尽管蛋白质在对照水平下表达。虽然连接蛋白43的分布没有改变，但总蛋白水平降低，并观察到磷酸化的变化。桥粒胶原蛋白-2a中的截短突变体缺乏结合斑珠蛋白。此外，桥粒胶蛋白-2a直接与连接蛋白43相互作用的能力被突变消除。未发现桥粒芯糖蛋白-2错义改变的致病潜力。观察到的间隙连接蛋白表达和磷酸化的异常，这之前的一个明显的心脏表型，可能是负责缓慢的心肌传导在这个病人。在分子水平上，桥粒胶原-2a突变体的结合特性改变可能有助于连接蛋白43的变化。特别是，新发现的桥粒胶原-2a亚型和连接蛋白43之间的相互作用提供了新的见解桥粒和缝隙连接之间的分子联系。
Cellular adhesion mediated by cardiac desmosomes is a prerequisite for proper electric propagation mediated by gap junctions in the myocardium. However, the molecular principles underlying this interdependence are not fully understood. The purpose of this study was to determine potential causes of right ventricular conduction abnormalities in a patient with borderline diagnosis of arrhythmogenic right ventricular cardiomyopathy. To assess molecular changes, the patient's myocardial tissue was analyzed for altered desmosomal and gap junction (connexin43) protein levels and localization. In vitro functional studies were performed to characterize the consequences of the desmosomal mutations. Loss of plakoglobin signal was evident at the cell junctions despite expression of the protein at control levels. Although the distribution of connexin43 was not altered, total protein levels were reduced and changes in phosphorylation were observed. The truncation mutant in desmocollin-2a is deficient in binding plakoglobin. Moreover, the ability of desmocollin-2a to directly interact with connexin43 was abolished by the mutation. No pathogenic potential of the desmoglein-2 missense change was identified. The observed abnormalities in gap junction protein expression and phosphorylation, which precede an overt cardiac phenotype, likely are responsible for slow myocardial conduction in this patient. At the molecular level, altered binding properties of the desmocollin-2a mutant may contribute to the changes in connexin43. In particular, the newly identified interaction between the desmocollin-2a isoform and connexin43 provides novel insights into the molecular link between desmosomes and gap junctions.
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影响因子：
4.8
作者：
Meng, JJ;Bornslaeger, EA;Ip, W
通讯作者：
Ip, W
影响因子：
37.8
作者：
Lambiase, P. D.;Ahmed, A. K.;McKenna, W. J.
通讯作者：
McKenna, W. J.
影响因子：
3.3
作者：
Sasano, Chieko;Honjo, Haruo;Kodama, Itsuo
通讯作者：
Kodama, Itsuo
DOI：
10.1111/j.1540-8167.1998.tb00133.x
发表时间：
1998-09-01
影响因子：
2.7
作者：
Schilling, RJ;Davies, DW;Peters, NS
通讯作者：
Peters, NS
DOI：
10.1042/bj20082319
发表时间：
2009-04-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Solan JL;Lampe PD
通讯作者：
Lampe PD