Functional characterization of a Central Core Disease RyR1 mutation (p.Y4864H) associated with quantitative defect in RyR1 protein

Abstract : BACKGROUND: Central Core Disease (CCD) is a congenital myopathy often resulting from a mutation in RYR1 gene. Mutations in RyR1 can increase or decrease channel activity, or induce a reduction in the amount of protein. The consequences of a single mutation are sometimes multiple and the analysis of the functional effects is complex. OBJECTIVE: The consequences of the p.Y4864H mutation identified in a CCD patient have been studied regarding both RyR1 function and amount. METHODS: The amount of RyR1 in human and mouse muscles was evaluated using qRT-PCR and quantitative Western blot, and calcium release was studied using calcium imaging on primary cultures. The results were compared between human and mouse. RESULTS: The p.Y4864H mutation induced an alteration of calcium release, and in addition was associated to a reduction in the amount of RyR1 in the patient’s muscle. This suggests two possible pathophysiological mechanisms: the alteration of calcium release could result from a modification of the channel properties of RyR1 or from a RyR1 reduction. In order to discriminate between the two hypotheses, we used the heterozygous RyR1 knockout (RyR1+/-) mouse model showing a comparable RyR1 protein reduction. No reduction in calcium release was observed in primary muscle culture from these mice, and no muscle weakness was measured. CONCLUSIONS: Because the reduction in the amount of RyR1 protein has no functional consequences in the murine model, the muscle weakness observed in the patient is most likely the result of a modification of the calcium channel function of RyR1 due to the p.Y4864H mutation.
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J. Neuromuscular Diseases, 2015, 202 (4), pp.421-432. 〈10.3233/JND-150073〉
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Marine Cacheux, Ariane Blum, Muriel Sébastien, Julie Brocard, Kamel Mamchaoui, et al.. Functional characterization of a Central Core Disease RyR1 mutation (p.Y4864H) associated with quantitative defect in RyR1 protein. J. Neuromuscular Diseases, 2015, 202 (4), pp.421-432. 〈10.3233/JND-150073〉. 〈inserm-01216714〉

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