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Lookup NU author(s): Professor Volker StraubORCiD
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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. © American Neurological Association.
Author(s): Wilmshurst J, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Müller C, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling J, Al-Sarraj S, Treves S, Abbs S, Manzur A, Sewry C, Muntoni F, Jungbluth H
Publication type: Article
Publication status: Published
Journal: Annals of Neurology
Year: 2010
Volume: 68
Issue: 5
Pages: 717-726
Print publication date: 13/09/2010
ISSN (print): 0364-5134
ISSN (electronic): 1531-8249
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/ana.22119
DOI: 10.1002/ana.22119
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