title: Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene.
abstract: The skeletal muscle ryanodine receptor plays a crucial role in excitation-contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca(2+) release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital for Children, London, UK.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lillis
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Loy
authors.forename: Farshid
authors.initials: F
authors.lastname: Ghassemi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rose
authors.forename: Fiona
authors.initials: F
authors.lastname: Norwood
authors.forename: Kerry
authors.initials: K
authors.lastname: Mills
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Russell J M
authors.initials: RJ
authors.lastname: Lane
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: Emma
authors.initials: E
authors.lastname: Matthews
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Stefan
authors.initials: S
authors.lastname: Buk
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D000328:Adult; D001120:Arginine / Q000235:genetics; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis / Q000379:methods; D003576:Electron Transport Complex IV / Q000187:drug effects; D005192:Family Health; D005260:Female; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology*; D009135:Muscular Diseases / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010726:Phosphodiesterase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D014316:Tritium; D012433:Ryanodine; D002110:Caffeine; D001120:Arginine; D003576:Electron Transport Complex IV; D008239:Lysine; D002118:Calcium