KATNAL2 dysfunction impairs microtubule dynamics and contributes to syndromic neurodevelopmental disease.
11 affiliations
- 1İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, Mithatpaşa Street No: 58/5, Balçova, İzmir 35340, Türkiye.
- 2İzmir Biomedicine and Genome Center, Mithatpaşa Street No: 58/5, Balçova, İzmir 35340, Türkiye.
- 3Department of Paediatric Neurology, School of Medicine, Dokuz Eylül University, Mithatpaşa Street No: 1606, Balçova, İzmir 35340, Türkiye.
- 4Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.
- 5Division of Neurology, Department of Medicine, The Ottawa Hospital Civic Campus, 1053 Carling Avenue, Ottawa, ON K1Y 4E9, Canada.
- 6Eric Poulin Center for Neuromuscular Disease, Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
- 7Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Mathildenstr. 1, 79106 Freiburg, Germany.
- 8Centro Nacional de Análisis Genómico (CNAG), Baldiri Reixac 4, Barcelona Science Park - Tower I, 08028 Barcelona, Spain.
- 9Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Robinson Way CB2 0PY, Cambridge, United Kingdom.
- 10Pediatric Neurology Clinic, Private Practice, Mahabad Boulevard, Kayapınar, Diyarbakır 21070, Türkiye.
- 11Department of Medical Biology, School of Medicine, Dokuz Eylül University, Mithatpaşa Street No: 1606, Balçova, İzmir 35340, Türkiye.
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.
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BibTeX
@article{sonmezler2026katnal2,
title = {{KATNAL2 dysfunction impairs microtubule dynamics and contributes to syndromic neurodevelopmental disease.}},
author = {Ece Sönmezler and Semra Hız Kurul and Ozlem Erez and Burcu Ekinci and Tutku Yaraş and Leman Binokay and Gökhan Karakülah and Hanns Lochmüller and Rita Horvath and Ahmet Yaramış and Gulcin Cakan-Akdogan and Yavuz Oktay},
journal = {Human molecular genetics},
year = {2026},
month = oct,
doi = {10.1093/hmg/ddag102},
url = {https://europepmc.org/article/MED/42905887},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - KATNAL2 dysfunction impairs microtubule dynamics and contributes to syndromic neurodevelopmental disease.
AU - Ece Sönmezler
AU - Semra Hız Kurul
AU - Ozlem Erez
AU - Burcu Ekinci
AU - Tutku Yaraş
AU - Leman Binokay
AU - Gökhan Karakülah
AU - Hanns Lochmüller
AU - Rita Horvath
AU - Ahmet Yaramış
AU - Gulcin Cakan-Akdogan
AU - Yavuz Oktay
PY - 2026
DA - 2026/10/01
JO - Human molecular genetics
DO - 10.1093/hmg/ddag102
UR - https://europepmc.org/article/MED/42905887
AB - 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.
SN - 0964-6906
SN - 1460-2083
ER -