A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation.
BACKGROUND
Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation.


METHODS
The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation.


RESULTS
All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression.


CONCLUSIONS
The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.
Borgatti
R
R
Divisione di Neuroriabilitazione 1, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy. borgatti@bp.lnf.it
Zucca
C
C
Cavallini
A
A
Ferrario
M
M
Panzeri
C
C
Castaldo
P
P
Soldovieri
M V
MV
Baschirotto
C
C
Bresolin
N
N
Dalla Bernardina
B
B
Taglialatela
M
M
Bassi
M T
MT
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance / Q000235:genetics; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000235:genetics; D020936:Epilepsy, Benign Neonatal / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D015640:Ion Channel Gating; D017136:Ion Transport; D051658:KCNQ2 Potassium Channel; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011487:Protein Conformation; D021122:Protein Subunits; D011782:Quadriplegia / Q000235:genetics; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits