Consequences of a novel caveolin-3 mutation in a large German family
Consequences of a novel caveolin-3 mutation in a large German family
复制标题
DOI：
10.1002/ana.10442
复制
发表时间：
2003-02-01
影响因子：
11.2
通讯作者：
Schröder, R
中科院分区：
文献类型：
--
作者：
Fischer, D;Schroers, A;Schröder, R
染色体3 p25上的人小窝蛋白-3基因（cav-3）突变已在肢带型肌营养不良症、波纹肌病、高CK血症和远端肌病中描述。在这里，我们描述了一个在cav-3基因的密码子27中存在一种新的杂合突变（GAC->GAA）的德国大家族的遗传学、肌肉病理学和临床发现。这种错义突变导致Cav-3蛋白的N-末端区域中的氨基酸从天冬酰胺变为谷氨酸（Asp 27 Glu），这导致骨骼肌组织中Cav-3蛋白表达的急剧降低。与常染色体显性遗传方式一致，在报道的家族中发现这种新的cav-3突变与神经肌肉受累共分离。Cav-3缺陷肌肉的超微结构分析显示质膜的异常折叠以及肌膜下区域的多个囊泡结构。对来自三代携带cav-3新突变的九名受试者进行神经系统检查，发现了明显的波纹肌疾病证据。然而，这9例患者中只有2例表现出孤立的波动性肌肉疾病体征，无肌肉无力或萎缩，而5例有远端肌病的其他体征，2例符合并存肢带型肌营养不良的诊断标准。这些发现表明，即使在同一家族中，人类cav-3基因的突变也会导致不同和重叠的临床表型。小窝蛋白病的不同临床表型可能归因于迄今为止未鉴定的受影响患者个体遗传背景中的修饰因子/基因。
Mutations in the human caveolin-3 gene (cav-3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC-->GAA) in codon 27 of the cav-3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N-terminal region of the Cav-3 protein, which leads to a drastic decrease of Cav-3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav-3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav-3-deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav-3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients.