KCNT1 (Slack/Slo2.2) and KCNT2 (Slick/Slo2.1) Dysregulation in Intellectual Disability and Behavioral Phenotypes: A Systematic Review.

Abstract

Potassium channels, particularly the sodium-activated Slo2 (Slack/KCNT1) channels, play a critical role in regulating neuronal excitability and protein synthesis. Emerging evidence suggests a strong association between Slo2 channel dysfunction and the development of intellectual disability (ID), including conditions like Fragile X syndrome and early-onset epileptic encephalopathies. This systematic review was designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Studies focusing on molecular, genetic, physiological, or clinical aspects of Slo2 channel function, regulation, or associated disorders were considered. A comprehensive literature search was conducted across multiple electronic databases: PubMed, Europe PubMed Central, Semantic Scholar, Directory of Open Access Journals (DOAJ), ScienceDirect, and Google Scholar. Search terms combined keywords and Medical Subject Headings (MeSH) relevant to Slo2 channels, KCNT1/KCNT2, sodium-activated potassium channels, ID, and neurological disorders. In total, eight studies met the inclusion criteria and were included in the final synthesis. This systematic review synthesizes findings from eight key studies published between 2010 and 2025, encompassing experimental animal models, narrative reviews, and molecular investigations with full-text availability. Each included study underwent methodological quality assessment using validated critical appraisal tools appropriate to its design. Quality assessments were performed using tools such as AMSTAR 2 applied for systematic reviews, cell study-OHAT-inspired for cell experimental studies, and SYRCLE's RoB for animal studies. The review highlights the dual impact of both gain- and loss-of-function KCNT mutations on cognitive function, with gain-of-function mutations often associated with more severe phenotypes. It further explores the molecular mechanisms involving FMRP and CYFIP1 interactions with Slack channels, implicating dysregulated protein translation as a contributor to ID. The literature shows that Slo2 potassium channels are implicated in ID, with both gain- and loss-of-function mutations contributing to cognitive impairment. The molecular mechanisms linking these mutations to clinical phenotypes remain incompletely defined. The findings support a growing consensus that Slo2 channelopathies represent a significant and under-recognized cause of neurodevelopmental impairment, warranting further translational research and therapeutic exploration.