Klein, Andrea and Lillis, Suzanne and Munteanu, Iulia and Scoto, Mariacristina and Zhou, Haiyan and Quinlivan, Ros and Straub, Volker and Manzur, Adnan Y and Roper, Helen and Jeannet, Pierre-Yves and Rakowicz, Wojtek and Jones, David Hilton and Jensen, Uffe Birk and Wraige, Elizabeth and Trump, Natalie and Schara, Ulrike and Lochmuller, Hanns and Sarkozy, Anna and Kingston, Helen and Norwood, Fiona and Damian, Maxwell and Kirschner, Janbernd and Longman, Cheryl and Roberts, Mark and Auer-Grumbach, Michaela and Hughes, Imelda and Bushby, Kate and Sewry, Caroline and Robb, Stephanie and Abbs, Stephen and Jungbluth, Heinz and Muntoni, Francesco (2012) Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Human mutation, 33 (6). pp. 981-8. ISSN 1098-1004. This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDsFull text not available from this repository.
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 multi-minicores, 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.
|Additional Information:||This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDs|
|Subjects:||QC-QM General sciences|
|Divisions:||Womens and Childrens > Paediatrics|
|Depositing User:||Sophie Rollason|
|Date Deposited:||11 Jun 2014 13:09|
|Last Modified:||11 Jun 2014 13:09|
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