New mutation of the Na channel in the severe form of potassium-aggravated myotonia.
Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF-hand calcium-binding motif in the intracellular C-terminus. A functional analysis of the mutant channel using the voltage-clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C-terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666-673, 2009.
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Tomoya
T
Kubota
Masanobu
M
Kinoshita
Ryogen
R
Sasaki
Futoshi
F
Aoike
Masanori P
MP
Takahashi
Saburo
S
Sakoda
Kazuhiko
K
Hirose
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D001703:Biophysics; D002461:Cell Line, Transformed; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004558:Electric Stimulation / Q000379:methods; D004576:Electromyography / Q000379:methods; D005192:Family Health; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D007564:Japan / Q000208:ethnology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D008958:Models, Molecular; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D016297:Mutagenesis, Site-Directed / Q000379:methods; D020125:Mutation, Missense / Q000235:genetics*; D020967:Myotonic Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D005973:Glutamine; D018698:Glutamic Acid; D000251:Adenosine Triphosphatases