title: 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.
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire and Centre de Référence des Maladies Neuro-Musculaires, CHU Grenoble, Grenoble, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marty
authors.forename: Julien
authors.initials: J
authors.lastname: Faure
authors.forename: Claudia
authors.initials: C
authors.lastname: Castiglioni
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Brigitte
authors.initials: B
authors.lastname: Estournet
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
authors.forename: Norma
authors.initials: N
authors.lastname: Romero
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerriere
authors.forename: Leila
authors.initials: L
authors.lastname: Lazaro
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Annick
authors.initials: A
authors.lastname: Rossi
authors.forename: Anneke
authors.initials: A
authors.lastname: Van der Kooi
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Corien
authors.initials: C
authors.lastname: Verschuuren
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
mesh_terms: D005260:Female; D020868:Gene Silencing; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel