Key result
Recessive core myopathies with quantitative RYR1 defects were universally caused by one recessive null allele, with phenotypic severity depending on the nature of the mutation on the second allele.
Observational
Recessive core myopathies with quantitative defects in RYR1 expression are caused by a recessive null allele, with phenotypic severity depending on the second allele's mutation.
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Supports RYR1 null allele testing in core myopathies; leaves open phenotypic prediction by second-allele mutation type.
Mutations of the ryanodine receptor cause dominant and recessive forms of congenital myopathies with cores. Quantitative defects of RYR1 have been reported in families presenting with recessive forms of the disease and epigenic regulation has been recently proposed to explain potential maternal monoallelic silencing of the RYR1 gene. We investigated nine families presenting with a recessive form of the disease and showing a quantitative defect of RYR1 expression. Genetic analysis allowed the identification of a mutation on both alleles of the RYR1 gene for all patients, 15 being novel variants. We evidenced for all patients an alteration of the expression of the RYR1 gene caused by amorphic mutations responsible either for mRNA or protein instability. In seven families the variant present on the second allele was a missense mutation. In the remaining two families the second variant led to a hypomorphic expression of the RYR1 gene and was associated with a severe neonatal phenotype, pointing out the minimal amount of RYR1 needed for skeletal muscle function. Noticeably, a novel additional exon 3b was characterized in the most severely affected cases. This study showed that all cases presenting with a quantitative defect of RYR1 expression in our panel of patients affected by recessive core myopathies were caused by the presence of one recessive null allele and that variability of the phenotype depended on the nature of the mutation present on the second allele. Our study also indicated that presence of a second mutation must be investigated in sporadic cases or in dominant cases presenting with a familial clinical variability.
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Monnier et al. (2008) conducted an observational in Recessive structural congenital myopathies with cores. RYR1 mutations was evaluated on Identification of RYR1 mutations and their effect on gene expression and phenotype. Recessive core myopathies with quantitative RYR1 defects were universally caused by one recessive null allele, with phenotypic severity depending on the nature of the mutation on the second allele.
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