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Publications

Journal Article Epublish 1 citation

PubMed: 42351313 DOI: 10.1186/s40478-026-02351-6

A rare missense variant impacting NEK1 kinase function is associated with ALS.

Acta Neuropathol Commun 14(1)

Authors: David Brenner, Anna Ponomarenko, Iris Petrut, Sofia Beyrle, Matilde Contardo, Isabel Loss, Constantin Radke, Jonas Frank, Eleni Zimmer, Matthias Schlesner, Pascal Achenbach, Wendy Scheveneels, Amr Aly, Hülya Nazlican, Jasper Hesebeck-Brinkmann, Patrick Oeckl, Kathrin Müller, Reiner Siebert, Tobias Böckers, Kristel van Eijk, Jan Veldink, Alexander Kleger, Medhanie Mulaw, Peter M Andersen, Karin Forsberg, Jochen H Weishaupt, Seyed Babak Loghmani, Thorsten Grehl, Philip van Damme, Joachim Weis, Alberto Catanese

Affiliations

  • Department of Neurology, University Hospital Ulm, 89081, Ulm, Germany.
  • Center for Rare Diseases (ZSE) Ulm, Ulm University Hospital Center for Rare Diseases, 89081, Ulm, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Ulm site, 89081, Ulm, Germany.
  • Institute of Anatomy and Cell Biology, Ulm University School of Medicine, 89081, Ulm, Germany.
  • Department of Neurosciences, Laboratory of Neurobiology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000, Leuven, Belgium.
  • VIB, Center for Brain & Disease Research, 3001, Leuven, Belgium.
  • Department of Neurology, University Hospital Ulm, 89081, Ulm, Germany.
  • Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany.
  • Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, 86159, Augsburg, Germany.
  • Institute of Molecular Oncology and Stem Cell Biology (IMOS), Ulm University Hospital, 89081, Ulm, Germany.
  • Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Department of Neurology, Centre for ALS and Other Motor Neuron Disorders, Alfried Krupp Krankenhaus Rüttenscheid, 45131, Essen, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Ulm site, 89081, Ulm, Germany.
  • Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
  • Center for Rare Diseases (ZSE) Ulm, Ulm University Hospital Center for Rare Diseases, 89081, Ulm, Germany.
  • Core Facility Organoids, Ulm University, 89081, Ulm, Germany.
  • Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands.
  • Division of Interdisciplinary Pancreatology, Department of Internal Medicine I, Ulm University Hospital, 89081, Ulm, Germany.
  • Unit for Single-Cell Genomics, Medical Faculty, Ulm University, 89081, Ulm, Germany.
  • Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
  • Department of Neurology, University Hospitals Leuven, 3000, Leuven, Belgium.
  • German Center for Neurodegenerative Diseases (DZNE), Ulm site, 89081, Ulm, Germany.
  • Institute of Anatomy and Cell Biology, Ulm University School of Medicine, 89081, Ulm, Germany.
  • Institute of Neuroanatomy, University Clinic RWTH Aachen, Wendlingweg 2, 52074, Aachen, Germany.

Abstract

Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.

MeSH

Neurons, Motor Neurons, Phenotype, Nima-Related Kinases, Nima-Related Kinase 1, Therapeutics, Nervous System Diseases, Protein Serine-Threonine Kinases