Molecular mechanisms and phenotypic variation in RYRI=related congenital myopathies

Dominant mutations in the skeletal muscle ryanodine receptor (RYRI) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYRI 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 RYRI 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 RYRI mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYRI involvement. We have identified 25 RYRI 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 RYRI C-terminal exons 101 and 102. In contrast, the 13 recessive RYRI mutations were distributed evenly along the entire RYRI gene and were associated with a wide range of clinicopathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyRI protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyRI expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyRI 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 RYRI-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyRI calcium release channel.