KATNAL2 dysfunction impairs microtubule dynamics and contributes to syndromic neurodevelopmental disease
Year: 2026
Type: article
Abstract: 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 fibroblasts and differentiated them into neural progenitor cells (NPCs) for quantitative immunofluorescence analyses of microtubule organization, microtubule regulatory proteins, and transcriptome profiling. In parallel, we generated CRISPR/Cas9 katnal2 zebrafish crispants 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/cytokinetic 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 a zebrafish model provide functional evidence linking the p.(Ser464Pro) variant to an expanded syndromic neurodevelopmental phenotype.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddag102
Institutions: Dokuz Eylül University, Izmir Biomedicine and Genome Center, University of Ottawa, University of Freiburg, Children's Hospital of Eastern Ontario, Ottawa Hospital, University Medical Center Freiburg, Centro Nacional de Análisis Genómico, uOttawa Brain and Mind Research Institute, Parc Científic de Barcelona, University of Cambridge
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: LifeArc, UK Research and Innovation, National Institute for Health and Care Research, Department of Health and Social Care, Ataxia UK, European Commission, Rosetrees Trust, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, HORIZON EUROPE Framework Programme, Medical Research Council, NIHR Cambridge Biomedical Research Centre
Awards: G1977987814, G2228563315, G2493601830, G2537968379, G2920001861, G3602036837, G3777639711, G4395209027, G4753630297, Katanin-A Benzeri Protein 2 (Katanin-Like 2) KATNAL2 Geninde İlk Kez Görülen Bir Yanlış Anlam Mutasyonunun Etkilerinin Hasta Fibroblastları ve Bunlardan Türetilen Hücrelerde İşlevsel Analiz Yöntemleri ile İncelenmesi, Targeting the cellular metabolism to treat tissue-specific mitochondrial diseases, MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases, G6401263891, G6746949437, Boosting the Rare Disease research and innovation capacity of the Izmir Biomedicine and Genome Center, G7100031956, G724433139, G7798797775, Probing Star Formation and Galaxy Evolution with Gamma-Ray Bursts, G84326791, G864407001, G8875776916
OpenAlex ID: W7223144173