Recent insights into IQSEC2 disease are summarized in this review as follows: (1) Exome sequencing of IQSEC2 patient DNA has led to the identification of numerous missense mutations that delineate at least six and possibly seven essential functional domains present in the IQSEC2 gene. (2) Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated the presence of autistic-like behavior and epileptic seizures in affected animals; however, seizure severity and etiology appear to vary considerably between models. (3) Studies in IQSEC2 KO mice reveal that IQSEC2 is involved in inhibitory as well as stimulatory neurotransmission. The overall picture appears to be that mutated or absent IQSEC2 arrests neuronal development, resulting in immature neuronal networks. Subsequent maturation is aberrant, leading to increased inhibition and reduced neuronal transmission. (4) The levels of Arf6-GTP remain constitutively high in IQSEC2 knockout mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle. (5) A new therapy that has been shown to reduce the seizure burden for the IQSEC2 A350V mutation is heat treatment. Induction of the heat shock response may be responsible for this therapeutic effect.
Keywords: Arf6-GTP; IQSEC2; heat shock.