KCNQ1 disruption alters human neuronal development through mitochondrial and insulin signalling pathways
KCNQ1 encodes a voltage-gated potassium channel implicated in peripheral and neurological disorders, but its role in human neurodevelopment remains unclear. We generated KCNQ1 knockout (KO) human induced pluripotent stem cells and differentiated them into neural stem cells (NSCs) and cortical neurons. KCNQ1-deficient NSCs show impaired neurite outgrowth, linked to reduced cell adhesion and disrupted neural cell adhesion molecule signalling, a phenotype reproduced by pharmacological KCNQ1 inhibition. Multi-omics and follow-up analyses reveal mitochondrial dysfunction, including reduced mitochondrial copy number and ATP synthase expression. KO cells also show impaired insulin signalling, with diminished insulin receptor gene expression and altered RAS-MAPK and PI3K-AKT pathways. In differentiated neuronal cultures, KCNQ1 loss decreases synaptic activity and maintains an immature transcriptional profile. Together, these findings identify a role for KCNQ1 in regulating cell adhesion, mitochondrial function, insulin signalling, and neuronal maturation, expanding our understanding of processes that may contribute to neurological manifestations associated with KCNQ1-related disorders.
Authors
- Jeffrey Colm Glennon (ORCID: https://orcid.org/0000-0002-2371-0422)
- Ralph Röth (ORCID: https://orcid.org/0000-0002-5032-3348)
- Naeem Ahmad (ORCID: https://orcid.org/0000-0002-6523-492X)
- Gudrun Rappold (ORCID: https://orcid.org/0000-0002-3126-1508)
- Ágota Apáti (ORCID: https://orcid.org/0000-0003-0380-8139)
- Baran E. Güler (ORCID: https://orcid.org/0000-0001-7967-9041)
- János Réthelyi (ORCID: https://orcid.org/0000-0002-3641-012X)
- Barbara Franke (ORCID: https://orcid.org/0000-0003-4375-6572)
- Joanna Widomska
- Simone Berkel (ORCID: https://orcid.org/0000-0002-5134-2217)
- Marcin Luzarowski (ORCID: https://orcid.org/0000-0002-2115-0468)
- Claudio Acuna (ORCID: https://orcid.org/0000-0002-8849-6260)
- Karin Burau (ORCID: https://orcid.org/0009-0008-6814-2298)
- Katalin Vincze
- Daniela Mauceri (ORCID: https://orcid.org/0000-0003-1225-4633)
- Dorothea Schall
- Linda Blaier
- Siamand Alibrahim
- Chang Liu
- Mahmudul Hasan (ORCID: https://orcid.org/0009-0001-8577-6128)
- Geert Poelmans
- Simone Macri
- Mairéad Sullivan
Institutions
- University College Dublin (IE)
- Semmelweis University (HU)
- National Institute for Biotechnology and Genetic Engineering (PK)
- Radboud University Nijmegen (NL)
- Philipps University of Marburg (DE)
- Heidelberg University (DE)
- Istituto Superiore di Sanità (IT)
- University Hospital Heidelberg (DE)
- Radboud University Medical Center (NL)
- Institute of Human Genetics (PL)
- Chica and Heinz Schaller Foundation (DE)
- DKFZ-ZMBH Alliance (DE)
- Donders Institute for Brain, Cognition and Behaviour (NL)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-10-13
- DOI
- https://doi.org/10.1038/s42003-026-11111-0
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- University College Dublin
- Deutscher Akademischer Austauschdienst
- Irish Research Council
- Bundesministerium für Bildung und Forschung
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Chica and Heinz Schaller Foundation
- Horizon 2020 Framework Programme