4.6 Article

LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin

期刊

HUMAN GENETICS
卷 131, 期 7, 页码 1123-1135

出版社

SPRINGER
DOI: 10.1007/s00439-011-1132-4

关键词

-

资金

  1. National Institutes of Health [R01NS049117-01]
  2. Muscular Dystrophy Association of America
  3. Myasthenia Gravis Foundation of California
  4. Instituto de Salud Carlos III, Fondo de Investigacion Sanitaria, Madrid, Spain [FIS PI10/02628, RD09/0076/00011]
  5. National Center for Research Resources, National Institutes of Health [C06 RR17348-01]
  6. MRC [G0701521] Funding Source: UKRI
  7. Medical Research Council [G0701521] Funding Source: researchfish

向作者/读者索取更多资源

We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by > 100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by similar to tenfold. Surprisingly, the V1727F mutant also displayed increased binding to alpha-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to alpha-dystroglycan, mimics non-neural (z-) agrin and are important determinants of the pathogenesis of the disease.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据