Epidermolysis bullosa: novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy.
Epidermolysis bullosa: novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy.
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DOI：
10.1046/j.1523-1747.2000.00880.x
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发表时间：
2000-02
期刊：
影响因子：
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通讯作者：
F. Rouan;L. Pulkkinen;Guerrino Meneguzzi;Sal LaForgia;Patrice Hyde;Dae Un Kim;Gabriele Richard;Jouni Uitto
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文献类型：
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作者：
F. Rouan;L. Pulkkinen;Guerrino Meneguzzi;Sal LaForgia;Patrice Hyde;Dae Un Kim;Gabriele Richard;Jouni Uitto
大疱性表皮松解症（EB）伴迟发性肌营养不良症（EB- md）是由PLEC1基因突变引起的EB的半染色体变异。注意到肌肉受累的发病年龄从婴儿期到生命的第四个十年不等。患者皮肤和肌肉活检的免疫荧光染色通常为阴性抗体识别粘连蛋白，一个大的细胞骨架相关的锚定蛋白。在这项研究中，我们报道了两个EB家族中新的凝集素突变。在这两个家庭中，先证者都是一个新生儿，患有新生儿起泡，目前还没有肌肉无力的证据。分离外周血DNA，并通过异源双工扫描策略、蛋白截断试验（PTT）和/或直接测序plectin基因进行检测。其中一个先证子为无义突变E2005X/K4460X的复合杂合子，第二个家族的先证子为缺失突变5083delG/2745-9del21的复合杂合子，后者突变在22内含子/ 23外显子边界从-9延伸到+12。突变K4460X和5083delG在亲本中均不存在，因此是从头开始的事件。在这两种情况下，通过微卫星标记分析排除了非父系关系。预计终止密码子突变会导致合成缺乏该蛋白羧基端球形结构域的截断蛋白，并可能导致相应mRNA的无义介导衰变。2745-9del21缺失突变消除了内含子22/外显子23连接处的剪接位点，预测了异常剪接事件。由于plectin缺乏症与肌营养不良有关，因此分子诊断plectin基因为评估这些有肌营养不良风险的患者提供了预后价值。
Epidermolysis bullosa (EB) with late-onset muscular dystrophy (EB-MD) is a hemidesmosomal variant of EB due to mutations in the plectin gene (PLEC1). The age of onset of muscle involvement has been noted to vary from infancy to the fourth decade of life. Immunofluorescence of the patients' skin and muscle biopsies is usually negative for staining with antibodies recognizing plectin, a large cytoskeleton-associated anchorage protein. In this study we report novel plectin mutations in two families with EB. In both families, the proband was a newborn with neonatal blistering with no evidence for muscle weakness as yet. Peripheral blood DNA was isolated and examined by heteroduplex scanning strategy, protein truncation test (PTT), and/or direct sequencing of the plectin gene. One of the probands was compound heterozygote for nonsense mutations E2005X/K4460X, and the proband in the second family was compound heterozygote for deletion mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at the intron 22/exon 23 border. The mutations K4460X and 5083delG were not present in either one of the parents, thus being de novo events. In both cases, nonpaternity was excluded by microsatellite marker analysis. The stop codon mutations are predicted to result in the synthesis of a truncated protein lacking the carboxy-terminal globular domain of the protein and possibly causing nonsense-mediated decay of the corresponding mRNA. The 2745-9del21 deletion mutation abolishes the splice site at the intron 22/exon 23 junction, predicting abnormal splicing events. Because plectin deficiency is associated with muscular dystrophy, molecular diagnostics of the plectin gene provides prognostic value in evaluation of these patients who appear to be at risk to develop muscular dystrophy.