Relevance to Autism

Systematic investigation of the phenotypic and molecular genetic data of 1,577 patients from the TRANSLATE NAMSE cohort who had undergone exome sequencing and were partially analyzed with next-generation phenotypic approaches in Schmidt et al., 2024 identified a de novo missense variant in the KCNN2 gene in an adult female.with autism and specific learning disability. A de novo missense variant that was predicted to be deleterious and a de novo nonsense variant in KCNN2 have recently been reported in ASD probands (Zhou et al., 2022; Fu et al., 2022). Mochel et al., 2020 described individuals with KCNN2-associated neurodevelopmental disorder, which was characterized by developmental delay, intellectual disability, behavioral disturbances, and movement disorders; two out of 10 of these individuals were reported to have autism spectrum disorder, while autistic features were reported in four other cases. Subsequent functional assessment of six variants identified in affected individuals in this report by patch-clamp electrophysiology found that five resulted in loss-of-function effects.

Molecular Function

Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits.

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