{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE346nnn/GSE346441/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE346441"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"KATNAL2 Dysfunction Impairs Microtubule Dynamics and Contributes to Syndromic Neurodevelopmental Disease","description":"Katanins are microtubule-severing ATPases. 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. In parallel, we generated a zebrafish CRISPR/Cas9 katnal2 model and assessed body patterning and axonal projections using the transgenic nbt:dsRed line. Patient iPSC-derived NPCs showed impaired interphase microtubule network organization with increased angular standard deviation in directionality and mitotic/cytokinesis abnormalities, including abnormal positioning of the microtubule-rich cytokinetic midbody region. In vivo, CRISPR/Cas9 katnal2 zebrafish crispants showed abnormal body patterning together with disorganized motor neuron and posterior lateral line nerve axonal projections. Together, these findings support KATNAL2 as a regulator of microtubule network organization and mitotic progression in human NPCs. Our data from patient-derived NPCs and zebrafish model provide functional evidence linking the p.(Ser464Pro) variant to an extended syndromic neurodevelopmental phenotype.","dates":{"publication":"2026/09/13"},"accession":"GSE346441","cross_references":{"GSM":["GSM10034282","GSM10034281"],"GPL":["24676"],"GSE":["346441"],"taxon":["Homo sapiens"]}}