Laboratoire de Neurogénétique de la Motricité, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Am J Hum Genet. 2010 Feb 12;86(2):213-21. doi: 10.1016/j.ajhg.2009.12.013. Epub 2010 Jan 21.
The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies.
最近描述的人类阴离子通道 Anoctamin（ANO）蛋白家族至少包含十个成员，其中许多成员被证明与钙激活的氯离子通道相对应。迄今为止，该基因家族中唯一报道的人类突变是罕见的骨骼疾病颌骨发育不良中的显性突变 ANO5（TMEM16E，GDD1）。我们已经在三个法裔加拿大家族中发现了ANO5 的隐性突变，这些突变导致近端肢体带肌营养不良症（LGMD2L），在荷兰和芬兰家族中导致远端非肌营养不良 Miyoshi 肌病（MMD3）。这些突变包括一个剪接位点、一个由法裔加拿大和荷兰病例共享的碱基对重复以及两个错义突变。剪接位点和重复突变引入了过早终止密码子，从而触发无意义介导的 mRNA 降解，表明存在潜在的失功能机制。LGMD2L 表型的特征是近端无力，表现为明显的不对称股四头肌和肱二头肌萎缩。MMD3 表型与远端无力有关，尤其是小腿肌肉。使用电子显微镜观察到两种表型都存在多灶性肌膜病变。ANO5 突变相关的表型异质性类似于 Dysferlin（DYSF）突变引起的 LGMD2B 和 Miyoshi 肌病（MMD1）。在一个 MMD3 受影响的个体中，通过膜封闭能力测定法在成纤维细胞上记录到缺陷的膜修复，如在 dysferlinopathies 中观察到的那样。尽管 ANO5 蛋白的功能尚不清楚，但它假定的钙激活氯离子通道功能可能为骨骼肌膜修复缺陷在肌肉营养不良中的作用提供重要的见解。
