Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene

Neuromuscul Disord. 2010 Mar;20(3):166-73. doi: 10.1016/j.nmd.2009.12.005. Epub 2010 Jan 18.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arginine / genetics
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism
  • Cell Line, Transformed
  • DNA Mutational Analysis / methods
  • Electron Transport Complex IV / drug effects
  • Family Health
  • Female
  • Humans
  • Lysine / genetics
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Muscle, Skeletal / pathology*
  • Muscular Diseases / classification
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology*
  • Mutation / genetics*
  • NAV1.4 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Phosphodiesterase Inhibitors / pharmacology
  • Ryanodine / metabolism
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sodium Channels / genetics
  • Transfection / methods
  • Tritium / metabolism

Substances

  • CACNA1S protein, human
  • Calcium Channels
  • Calcium Channels, L-Type
  • NAV1.4 Voltage-Gated Sodium Channel
  • Phosphodiesterase Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • SCN4A protein, human
  • Sodium Channels
  • Tritium
  • Ryanodine
  • Caffeine
  • Arginine
  • Electron Transport Complex IV
  • Lysine
  • Calcium