Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy
Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy
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DOI：
10.1161/circulationaha.105.583674
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发表时间：
2006-03-07
期刊：
影响因子：
37.8
通讯作者：
Rampazzo, A
中科院分区：
文献类型：
--
作者：
Pilichou, K;Nava, A;Rampazzo, A
背景-致心律失常性右室心肌病(ARVC)是一种遗传性心肌病，其特征是进行性心肌萎缩伴纤维脂肪替代。最近对血小板球蛋白、桥粒蛋白(DSP)和血小板亲和素-2(PKP2)基因的致病突变的发现导致了ARVC是由桥粒缺陷引起的假设。因此，我们在ARVC患者中进行了桥粒芯糖蛋白-2(DSG2)的筛查。方法与结果：在80例无关ARVC先证者中，26例携带DSP16%、PKP2(14%)和转化生长因子-β3(2.5%)基因突变，其余54例通过变性高效液相色谱和直接测序筛查DSG2突变。8例先证者中检出9例DSG2杂合性突变(错义5例，插入缺失2例，无义突变1例，剪接点突变1例)。所有先证者都符合特别工作组的ARVC标准。5例患者行心内膜心肌活检，发现纤维脂肪组织替代后心肌细胞广泛丢失。在3例患者中，进行了电子显微镜检查，显示间盘苍白，桥粒数量减少，细胞间隙扩大。结论--这是第一次在大量ARVC无关先证者中发现DSG2基因突变。心脏表型的临床特征是典型的ARVC特征，常累及左心室，形态上表现为纤维脂肪心肌置换和桥粒重塑。在40%的病例中，桥粒编码基因突变的存在证实了许多形式的ARVC是由于桥粒复合体的改变所致。
Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC.Methods and Results - In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-beta 3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations ( 5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening.Conclusions - This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.