Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.
KCNQ2 and KCNQ3 are two homologous K(+) channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.
Dedek
K
K
Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany.
Kunath
B
B
Kananura
C
C
Reuner
U
U
Jentsch
T J
TJ
Steinlein
O K
OK
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D004553:Electric Conductivity; D004594:Electrophysiology; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008297:Male; D009154:Mutation; D020385:Myokymia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013577:Syndrome; D014982:Xenopus laevis
D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated