Relevance to Autism

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200). Miceli et al. 2022 provided detailed clinical information on fifteen patients (14 novels and 1 previously published) with KCNQ2 p.Arg144 missense variants; all patients had developmental delay with prominent language impairment, and ten of these patients (67%) presented with autistic features. Furthermore, functional analysis of KCNQ2 p.Arg144 missense variants by whole-cell patch-clamp recordings in this report demonstrated that activation gating of homomeric mutant channels was left-shifted, suggesting gain-of-function effects.

Molecular Function

The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1).

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Model Summary

Mutant mice exhibit increased susceptibility to induced seizures, and rare spontaneous seizures as adults.

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