Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.
复制标题
DOI：
10.1016/j.jacc.2009.11.020
复制
发表时间：
2010-02-09
影响因子：
24
通讯作者：
Towbin, Jeffrey A.
中科院分区：
文献类型：
--
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.
明确致心肌病性右室心肌病的遗传基础。致心律失常性右心室心肌病（ARVC），以右心室纤维脂肪替代和心律失常为特征，可导致猝死。已知常染色体显性遗传、染色体畸变率降低和7个编码桥粒的致病基因。低反射率的基础是知之甚少。入组ARVC先证者和家族成员，获得血液，淋巴母细胞系永生化，提取DNA，进行桥粒编码基因的PCR扩增，PCR产物测序，并使用共聚焦免疫荧光显微镜和抗关键蛋白抗体研究患病组织样本的细胞间连接蛋白分布。我们在198例先证者中的38例（19%）中鉴定出21种斑嗜蛋白-2（PKP 2）变异，包括错义、无义、剪接位点和缺失/插入突变。家系显示出广泛的家族内变异性（严重的早发性疾病无症状个体）。在9/38的先证者中，鉴定了反式编码的PKP 2变体（复合杂合性）。对38名携带PKP 2变体的先证者进行了其他桥粒基因突变筛查;在16/38名PKP 2变体受试者（42%）中鉴定出第二种变体（双基因杂合性），包括桥粒斑蛋白（DSP，n=6）、桥粒芯蛋白-2（DSG 2，n=5）、斑嗜蛋白-4（PKP 4，n=1）和桥粒芯蛋白-2（DSC 2，n=1）。14/198例受试者（7%）发生非PKP 2桥粒基因杂合突变，包括DSP（n=4）、DSG 2（n=5）、DSC 2（n=3）和连接斑珠蛋白（JUP，n=2）。所有的变异都发生在保守区域，在700个种族匹配的对照中没有发现。免疫组化分析显示蛋白质结构异常。这些数据表明，ARVC的遗传基础包括复合和双基因杂合性降低的等位基因率。桥粒突变受试者的连接细胞结构紊乱证实ARVC是桥粒和细胞连接的疾病。
To define the genetic basis of arrhythmogenic right ventricular cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy (ARVC), characterized by right ventricular fibrofatty replacement and arrhythmias, causes sudden death. Autosomal dominant Inheritance, reduced penetrance, and 7 desmosome-encoding causative genes are known. The basis of low penetrance is poorly understood. ARVC probands and family members were enrolled, blood obtained, lymphoblastoid cell lines immortalized, DNA extracted, PCR amplification of desmosome-encoding genes performed, PCR products sequenced and diseased tissue samples studied for intercellular junction protein distribution using confocal immunofluorescence microscopy and antibodies against key proteins. We identified 21 variants in plakophilin-2 (PKP2) in 38 of 198 probands (19%), including missense, nonsense, splice site, and deletion/insertion mutations. Pedigrees showed wide intra-familial variability (severe early-onset disease to asymptomatic individuals). In 9/38 probands, PKP2 variants were identified that were encoded in trans (compound heterozygosity). The 38 probands hosting PKP2 variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16/38 subjects with PKP2 variants (42%) including desmoplakin (DSP, n=6), desmoglein-2 (DSG2, n=5), plakophilin-4 (PKP4, n=1), and desmocollin-2 (DSC2, n=1). Heterozygous mutations in non-PKP 2desmosomal genes occurred in 14/198 subjects (7%), including DSP (n=4), DSG2 (n=5), DSC2 (n=3), and junctional plakoglobin (JUP, n=2). All variants occurred in conserved regions; none were identified in 700 ethnic-matched controls. Immunohistochemical analysis demonstrated abnormalities of protein architecture. These data suggest that the genetic basis of ARVC includes reduced penetrance with compound and digenic heterozygosity. Disturbed junctional cytoarchitecture in subjects with desmosomal mutations confirms that ARVC is a disease of the desmosome and cell junction.
登录
查看更多内容
影响因子：
3.5
作者：
Cho, Yongkeun;Park, Taein;Park, Wee-Hyun
通讯作者：
Park, Wee-Hyun
影响因子：
3.7
作者：
Kaplan, SR;Gard, JJ;Saffitz, JE
通讯作者：
Saffitz, JE
影响因子：
3.5
作者：
Norgett, EE;Hatsell, SJ;Kelsell, DP
通讯作者：
Kelsell, DP
影响因子：
37.8
作者：
Dalal, D;Nasir, K;Calkins, H
通讯作者：
Calkins, H
影响因子：
37.8
作者：
MARCUS, FI;FONTAINE, GH;GROSGOGEAT, Y
通讯作者：
GROSGOGEAT, Y