Dominant mutations in the skeletal muscle
ryanodine receptor (
RYR1) gene are well-recognized causes of both
malignant hyperthermia susceptibility (MHS) and
central core disease (CCD). More recently, recessive
RYR1 mutations have been described in few congenital
myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive
RYR1 mutations exists, in most cases with recessive mutations the pattern of
muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital
myopathies associated with
RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of
RYR1 involvement. We have identified 25
RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the
RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive
RYR1 mutations were distributed evenly along the entire
RYR1 gene and were associated with a wide range of clinico-pathological phenotypes.
Protein expression studies in nine cases suggested a correlation between specific mutations,
RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal
RyR1 expression, individuals with more generalized weakness, multi-minicores and
external ophthalmoplegia had a pronounced depletion of the
RyR1 protein. The phenomenon of
protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related
myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the
RyR1 calcium release channel.