Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene.
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.
Zhou
Haiyan
H
Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital for Children, London, UK.
Lillis
Suzanne
S
Loy
Ryan E
RE
Ghassemi
Farshid
F
Rose
Michael R
MR
Norwood
Fiona
F
Mills
Kerry
K
Al-Sarraj
Safa
S
Lane
Russell J M
RJ
Feng
Lucy
L
Matthews
Emma
E
Sewry
Caroline A
CA
Abbs
Stephen
S
Buk
Stefan
S
Hanna
Michael
M
Treves
Susan
S
Dirksen
Robert T
RT
Meissner
Gerhard
G
Muntoni
Francesco
F
Jungbluth
Heinz
H
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
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