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- Title
Identification of four novelmutations in the C-terminal membrane spanning domain of the ryanodinereceptor 1: association with central core disease and alterationof calcium homeostasis.
- Authors
Tilgen, Nikola; Zorzato, Francesco; Halliger-Keller, Birgit; Muntoni, Francesco; Sewry, Caroline; Palmucci, Laura M.; Schneider, Christiane; Hauser, Erwin; Lehmann-Horn, Frank; Müller, Clemens R.; Treves, Susan
- Abstract
The skeletal muscle ryanodine receptor gene (RYR1; OMIM180901) on chromosome 19q13.1 encodes the skeletal muscle calciumrelease channel. To date, more than 25 missense mutations have beenidentified in RYR1 and are associated with centralcore disease (CCD; OMIM 117000) and/or the malignant hyperthermia susceptibilityphenotype (MHS1; OMIM 145600). The majority of RYR1 mutationsare clustered in the N-terminal hydrophilic domain of the protein. Onlyfour mutations have been identified so far in the highly conservedC-terminal region encoding the luminal/transmembrane domainof the protein which forms the ion pore. Three of these mutationshave been found to segregate with pure or mixed forms of CCD. Wehave screened the C-terminal domain of the RYR1 genefor mutations in 50 European patients, diagnosed clinically and/orhistologically as having CCD. We have identified five missense mutations (fourof them novel) in 13 index patients. The mutations cluster in exons101 and 102 and replace amino acids which are conserved in all knownvertebrate RYR genes. In order to study the functionaleffect of these mutations, we have immortalized B-lymphocytes fromsome of the patients and studied their [Ca2+]i homeostasis.We show that lymphoblasts carrying the newly identified RYR1 mutationsexhibit: (i) a release of calcium from intracellular stores in theabsence of any pharmacological activators of RYR; (ii) significantly smallerthapsigargin-sensitive intracellular calcium stores, compared tolymphoblasts from control individuals; and (iii) a normal sensitivityof the calcium release to the RYR inhibitor dantrolene. Our datasuggest the C-terminal domain of RYR1 as a hot spot for mutationsleading to the CCD phenotype. If the functional alterations of mutatedRYR channels observed in lymphoblastoid cells are also present in skeletalmuscles this could explain the predominant symptom of CCD, i.e.chronic muscle weakness. Finally, the study of calcium homeostasisin lymphoblastoid cells naturally expressing RYR1 mutations offersa novel non-invasive approach to gain insights into the pathogenesisof MH and CCD.
- Publication
Human Molecular Genetics, 2001, Vol 10, Issue 25, p2879
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/10.25.2879