Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro.
Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro.
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DOI：
10.1186/1471-2350-8-65
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发表时间：
2007-10-26
影响因子：
--
通讯作者：
Rampazzo A
中科院分区：
文献类型：
--
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
据报道，编码桥粒蛋白的基因突变可导致致心律失常的右室心肌病(ARVC)，这是一种常染色体显性疾病，其特征是进行性心肌萎缩伴纤维脂肪替代。我们对54个ARVC先证者进行了桥粒芯胶原-2(DSC2)的突变筛查，桥粒芯胶原是唯一在心脏组织中表达的桥粒芯胶原亚型。用变性高效液相色谱法和直接测序法进行突变筛查。为评价ARVC患者DSC2基因突变的致病潜能，将野生型和突变的DSC2基因克隆到真核表达载体中，获得绿色荧光蛋白(GFP)融合蛋白，并将其导入新生大鼠心肌细胞和HL-1细胞。我们在两个先证者和四个家庭成员中发现了两个杂合子突变(c.304G>；A(p.E102K)和c.1034T>；C(p.I345T))。两个突变p.E102K和p.I345T映射到与粘附性相互作用相关的N-末端区域。体外功能研究表明，与野生型DSC2不同，这两个N端突变体主要定位于细胞质中。N-末端区域的两个错义突变影响DSC2的正常定位，因此提示已报道的突变的潜在致病作用。识别与ARVC相关的其他DSC2突变可能会提高诊断的准确性，并可能对遗传咨询产生影响。
Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue. Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing. To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells. We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions. In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm. The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.
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影响因子：
158.5
作者：
THIENE, G;NAVA, A;PENNELLI, N
通讯作者：
PENNELLI, N
影响因子：
4.1
作者：
Syed, SEH;Trinnaman, B;Magee, AI
通讯作者：
Magee, AI
影响因子：
7.8
作者：
OZAWA, M;KEMLER, R
通讯作者：
KEMLER, R
影响因子：
39.3
作者：
Basso, Cristina;Czarnowska, Elzbieta;Rampazzo, Alessandra
通讯作者：
Rampazzo, Alessandra
影响因子：
37.8
作者：
Syrris, P;Ward, D;McKenna, WJ
通讯作者：
McKenna, WJ