Therrien Christian, Dodig Dubravka, Karpati George, Sinnreich Michael
Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec Canada H3A 2B4.
J Neurol Sci. 2006 Dec 1;250(1-2):71-8. doi: 10.1016/j.jns.2006.07.004. Epub 2006 Sep 22.
Dysferlin is a large sarcolemmal protein implicated in the repair of surface membrane tears in muscle cells. Mutations in dysferlin result in limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Using a cDNA based approach we identified eight new pathogenic dysferlin alleles. To better understand how missense mutations could lead to reduced or absent dysferlin expression levels, we mapped missense mutations from our own and from published databases (n=55) to the secondary protein structure of dysferlin, deduced by computerized structural prediction tools. We found the protein to be very sensitive to the alteration of residues that were predicted to be buried inside the protein structure. We identified seven putative C2 domains, one more than commonly reported, of both type I and type II topology in dysferlin. Missense mutations often affected those structures as well as residues that were highly conserved between members of the ferlin family. Thus, alteration of structurally important residues in dysferlin could lead to improper folding and degradation of the mutant protein.
dysferlin是一种大型肌膜蛋白，与肌肉细胞表面膜撕裂的修复有关。dysferlin基因突变会导致2B型肢带型肌营养不良症和宫下肌病。我们采用基于cDNA的方法鉴定出8个新的致病性dysferlin等位基因。为了更好地理解错义突变如何导致dysferlin表达水平降低或缺失，我们将来自我们自己以及已发表数据库（n = 55）的错义突变映射到通过计算机结构预测工具推导的dysferlin二级蛋白质结构上。我们发现该蛋白质对预测埋在蛋白质结构内部的残基的改变非常敏感。我们在dysferlin中鉴定出7个推定的C2结构域，比通常报道的多1个，包括I型和II型拓扑结构。错义突变常常影响这些结构以及ferlin家族成员之间高度保守的残基。因此，dysferlin中结构重要残基的改变可能导致突变蛋白折叠不当和降解。
