Interactions between genetic variants of SCN2A and KCNQ2 in the mouse and variants of SCN1A and SCN9A in patients provide models of potential genetic modifier effects in the more common human polygenic epilepsies.
The phenotypic spectrum associated with KCNQ2 mutations is probably broader than initially thought, as patients with severe epilepsies and developmental delay, or with Rolando epilepsy have been described.
We searched PubMed using the free text term search 'KCNQ2 AND Epilepsy' and identified additional records using PubMed Medical Subject Headings (MeSH).
Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal-infantile epilepsy.
In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
The open reading frame of the translated protein comprises 852 amino acids with 6 transmembrane segments and a pore motif between S5 and S6. rKCNQ2 shares 96% amino acid identity with human KCNQ2 in which mutations cause a form of epilepsy known as benign familial neonatal convulsions (BFNC).
Examples of that include the need to avoid specific drugs in Dravet syndrome and the ongoing investigations of the potential use of new directed therapies such as retigabine in KCNQ2-related epilepsies, quinidine in KCNT1-related epilepsies, and memantine in GRIN2A-related epilepsies.
The diminished activity of mutant KCNQ2 channels accounts for neonatal epilepsy and myokymia; the cellular locus of these effects may be axonal initial segments and nodes.
The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies.
The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials.
(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.
Our results demonstrate that variants in Scn2a, Kcnq2, and Scn8a can dramatically influence the phenotype of mice carrying the Scn1a-R1648H mutation and suggest that ion channel variants may contribute to the clinical variation seen in patients with monogenic epilepsy.
Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome.
With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, for example for KCNQ2 mutation related epilepsies, Dravet syndrome or tuberous sclerosis complex.
In addition to facilitating more effective mutation detection among BFNC patients, the results presented here provide the basis for analysing the role of KCNQ2 in other types of epilepsy.