Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores

Abstract

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.

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

“…It was recently found in two unrelated patients with recessive forms of CCD. 48 In contrast, another mutation from this group, p.Ala140Thr, is most likely a rare benign polymorphism similar to the only mutation from the third group, p.Ala4185Thr, which was predicted to be neutral by bioinformatic programs. This prediction is supported by the results of segregation analysis; p.Ala140Thr was identified in a second-degree relative of a proband, whereas the proband and another MHS relative did not carry this mutation.…”

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

“…2-4). Age-dependent changes in myofiber lesions have been suggested in isolated CCD cases in which no abnormalities or only minicores were found in muscle biopsies from younger patients, whereas cores were observed in subsequent muscle biopsies (5,27) or in muscle biopsies of affected parents (28,29). Nemaline rods have been detected in a few CCD cases (4-7).…”

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

“…However, there have been reports of at least 18 families with compound heterozygosity, as proven by haplotyping and/or segregation analysis. 4,7,30,[33][34][35][36] Nevertheless, the majority of the previously reported RYR1 recessive cases had a neonatal or childhood onset. Our report adds some more complexity to this picture and widens the phenotypic variability.…”

“…Accordingly, because RYR1 is a large gene, and mutation screening is often limited to the hotspot regions, it was previously recognized that autosomal-recessive cases are probably underestimated in the literature. 35 Although the genetic cause of the phenotype in some patients remains to be established, either due to RYR1 mutations, which are undetectable by routine methods, or to defects in other genes, our findings support the idea that RYR1 mutation screening should be considered in cases with adult-onset, mild muscle symptoms and histological findings compatible with CCD or MmD. Considering these inclusion criteria, the detection of RYR1 mutations in 3 of our 8 patients (38%) seems sufficiently relevant to validate our study approach.…”