title: Samaritan myopathy, an ultimately benign congenital myopathy, is caused by a RYR1 mutation.
abstract: Congenital myopathies describe a group of inherited muscle disorders with neonatal or infantile onset typically associated with muscle weakness, respiratory involvement and delayed motor milestones. We previously reported a novel congenital myopathy in an inbred Samaritan family. All patients displayed severe neonatal hypotonia and respiratory distress, and unlike other congenital myopathies, a constantly improving health status. As clinical and pathological data did not point to preferential candidate genes, we performed exome sequencing complemented by linkage analysis to identify the mutation causing the benign Samaritan congenital myopathy. We identified the homozygous p.Tyr1088Cys mutation in RYR1, encoding the skeletal muscle ryanodine receptor. This sarcoplasmic reticulum calcium channel is a key regulator of excitation-contraction coupling (ECC). Western blot and immunohistofluorescence revealed a significant decrease of the RYR1 protein level and an abnormal organization of skeletal muscle triad markers as caveolin-3, dysferlin and amphiphysin 2. RYR1 mutations are associated with different myopathies and malignant hyperthermia susceptibility. The index patient had mild hyperthermia following anesthesia, indicating that the inbred Samaritan population might be a risk group for this disorder. Our results suggest an aberrant ECC as the primary cause of this disease, and broaden the clinical consequences of RYR1 defects.
authors: Department of Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors: Johann
authors: J
authors: Böhm
authors: Esther
authors: E
authors: Leshinsky-Silver
authors: Stéphane
authors: S
authors: Vassilopoulos
authors: Stéphanie
authors: S
authors: Le Gras
authors: Tally
authors: T
authors: Lerman-Sagie
authors: Mira
authors: M
authors: Ginzberg
authors: Bernard
authors: B
authors: Jost
authors: Dorit
authors: D
authors: Lev
authors: Jocelyn
authors: J
authors: Laporte
mesh_terms: D015153:Blotting, Western; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020512:Myopathy, Central Core / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel