雷亚尔1
中心核心病
先天性肌病
错义突变
生物
肌肉活检
移码突变
复合杂合度
遗传学
病理
肌病
突变
兰尼定受体
医学
内质网
活检
基因
作者
Jo Wilmshurst,Suzanne Lillis,Haïyan Zhou,Komala Pillay,Howard Henderson,Wolfram Kreß,Clemens R. Müller,Alvin Ndondo,V Cloke,Thomas Cullup,Enrico Bertini,C Boennemann,Volker Straub,R. Quinlivan,James J. Dowling,Safa Al‐Sarraj,Susan Treves,Stephen Abbs,Adnan Manzur,Caroline A. Sewry,Francesco Muntoni,Heinz Jungbluth
摘要
Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM.We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations.The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings.Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.
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