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

Nicole Monnier, Isabelle Marty, Julien Faure, Claudia Castiglioni, Claude Desnuelle, Sabrina Sacconi, Brigitte Estournet, Ana Ferreiro, Norma Romero, Annie Laquerriere, Leila Lazaro, Jean Jacques Martin, Eva Morava, Annick Rossi, Anneke Van Der Kooi, Marianne De Visser, Corien Verschuuren, Joël Lunardi

Research output: Contribution to journalArticle

65 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)670-678
Number of pages9
JournalHuman mutation
Volume29
Issue number5
DOIs
StatePublished - May 2008

Keywords

  • Amorphic mutations
  • CCD
  • MmD
  • RYR1
  • Recessive core myopathies

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Monnier, N., Marty, I., Faure, J., Castiglioni, C., Desnuelle, C., Sacconi, S., Estournet, B., Ferreiro, A., Romero, N., Laquerriere, A., Lazaro, L., Martin, J. J., Morava, E., Rossi, A., Van Der Kooi, A., De Visser, M., Verschuuren, C., & Lunardi, J. (2008). Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores. Human mutation, 29(5), 670-678. https://doi.org/10.1002/humu.20696