KATNAL2 Dysfunction Impairs Microtubule Dynamics and Contributes to Syndromic Neurodevelopmental Disease

Dysfunction of katanin subunits has been implicated in impaired neurogenesis, morphogenesis, and neuronal migration. Although heterozygous variants in KATNAL2 (katanin-like 2), a known autism-spectrum disorder (ASD) risk gene, have been reported in patients with ASD or other neurodevelopmental disorders (NDD), the underlying cellular mechanisms remain incompletely defined.

Whole-exome sequencing (WES) identified a homozygous missense variant in KATNAL2 (NM_001387690.1: c.1390T>C; p.(Ser464Pro)) in a pediatric patient presenting with severe global developmental delay, intellectual disability, infantile-onset epilepsy, and autistic features, extending the phenotypic spectrum beyond prior autism-focused associations. To elucidate the cellular mechanisms underlying KATNAL2 dysfunction, we established induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts and differentiated them into neural progenitor cells (NPCs) for quantitative immunofluorescence analyses of microtubule organization, KATNAL2-associated microtubule regulatory network, and transcriptome profiling.