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Clinical and Genetic Findings in a Large Cohort of Patients with Ryanodine Receptor 1 Gene-Associated Myopathies

Lookup NU author(s): Professor Volker Straub, Professor Hanns Lochmuller, Dr Anna Sarkozy, Dr Fiona Norwood, Emerita Professor Katherine Bushby

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Abstract

Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multiminicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential. Hum Mutat 33: 981-988, 2012. (C) 2012 Wiley Periodicals, Inc.


Publication metadata

Author(s): Klein A, Lillis S, Munteanu I, Scoto M, Zhou HY, Quinlivan R, Straub V, Manzur AY, Roper H, Jeannet PY, Rakowicz W, Jones DH, Jensen UB, Wraige E, Trump N, Schara U, Lochmuller H, Sarkozy A, Kingston H, Norwood F, Damian M, Kirschner J, Longman C, Roberts M, Auer-Grumbach M, Hughes I, Bushby K, Sewry C, Robb S, Abbs S, Jungbluth H, Muntoni F

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2012

Volume: 33

Issue: 6

Pages: 981-988

Print publication date: 04/04/2012

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/humu.22056

DOI: 10.1002/humu.22056


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