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RYR1 mutations are a common cause of congenital myopathies with central nuclei.

Abstract：

OBJECTIVE: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. METHODS: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. RESULTS: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. INTERPRETATION: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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Wilmshurst JM,Lillis S,Zhou H,Pillay K,Henderson H,Kress W,Müller CR,Ndondo A,Cloke V,Cullup T,Bertini E,Boennemann C,Straub V,Quinlivan R,Dowling JJ,Al-Sarraj S,Treves S,Abbs S,Manzur AY,Sewry CA,Muntoni F,Jung

doi

10.1002/ana.22119

subject

Has Abstract

pub_date

2010-11-01 00:00:00

pages

717-26

issue

eissn

0364-5134

issn

1531-8249

journal_volume

pub_type

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RYR1 mutations are a common cause of congenital myopathies with central nuclei.