A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps

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  • dc.contributor.author Segarra Casas, Alba
  • dc.contributor.author Iruzubieta, Pablo
  • dc.contributor.author Kapetanovic, Solange
  • dc.contributor.author Hernández-Laín, Aurelio
  • dc.contributor.author Jericó, Ivonne
  • dc.contributor.author Fernández Torrón, Roberto
  • dc.contributor.author Maneiro, Miren
  • dc.contributor.author Marco Moreno, Pablo
  • dc.contributor.author Zelaya Huerta, M. Victoria
  • dc.contributor.author Rodríguez Santiago, Benjamín
  • dc.contributor.author Calafell i Majó, Francesc
  • dc.contributor.author Töpf, Ana
  • dc.contributor.author Straub, Volker
  • dc.contributor.author Vallejo Illarramendi, Ainara
  • dc.contributor.author López de Munain, Adolfo
  • dc.contributor.author Gallano, Pía
  • dc.contributor.author Gonzalez-Quereda, Lidia
  • dc.date.accessioned 2025-02-21T07:13:19Z
  • dc.date.available 2025-02-21T07:13:19Z
  • dc.date.issued 2025
  • dc.description.abstract Background and purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant. Methods: Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives. Results: Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non-specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype. Conclusion: Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.
  • dc.description.sponsorship This study was supported by Instituto de Salud Carlos III and FEDER, ‘Una manera de hacer Europa’, with the grants FIS PI18/01585 (LGQ and PG) and PI22/01859 (LGQ), MCIN/AEI/10.13039/501100011033 (PID20220-119780RB-I00, AVI) and Gobierno Vasco (GIU20/057 and 2,022,111,045, AVI). ASC was supported by the Ministerio de Universidades (Spain) with the grant FPU20/06692, and PMM was supported by a PhD fellowship from Fundacion Jesus De Gangoiti Barrera. MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, CureLGMD2i, LGMD2D Foundation and Kurt+Peter Foundation, Muscular Dystrophy UK and Coalition to Cure Calpain 3 (VS). Analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141 (VS). FC was supported by Agencia Estatal de Investigación ‘Unidad María de Maeztu’ (CEX2018-000792-M) and Agència de Gestió d'Ajuts Universitaris i de la Recerca (Generalitat de Catalunya, grant 2021SGR00466).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Segarra-Casas A, Iruzubieta P, Kapetanovic S, Hernández-Laín A, Jericó I, Fernández-Torrón R, et al. A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps. Eur J Neurol. 2025 Jan;32(1):e16471. DOI: 10.1111/ene.16471
  • dc.identifier.doi http://dx.doi.org/10.1111/ene.16471
  • dc.identifier.issn 1351-5101
  • dc.identifier.uri http://hdl.handle.net/10230/69666
  • dc.language.iso eng
  • dc.publisher Wiley
  • dc.relation.ispartof Eur J Neurol. 2025 Jan;32(1):e16471
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID20220-119780RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
  • dc.rights © 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword RYR1‐related myopathies
  • dc.subject.keyword Exercise intolerance
  • dc.subject.keyword HyperCKemia
  • dc.subject.keyword Myalgia
  • dc.title A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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