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

A correction to this paper has been published: the notice, 42477825, from Europe PMC.

Overview

Authors: David Brenner1,2,3, Anna Ponomarenko4, Iris Petrut4, Sofia Beyrle4, Matilde Contardo5,6, Isabel Loss1, Constantin Radke7, Jonas Frank8, Eleni Zimmer9, Matthias Schlesner8, Pascal Achenbach7, Wendy Scheveneels5,6, Amr Aly4,10,11, Hülya Nazlican12, Jasper Hesebeck-Brinkmann1, Patrick Oeckl1,3, Kathrin Müller13, Reiner Siebert2,14, Tobias Böckers3,4, Kristel van Eijk15
and 11 other authorsJan Veldink15, Alexander Kleger2,9,16,14, Medhanie Mulaw17, Peter M Andersen18, Karin Forsberg18, Jochen H Weishaupt1,2,3, Seyed Babak Loghmani1, Thorsten Grehl12, Philip van Damme5,19, Joachim Weis7, Alberto Catanese3,4,20
ORCID iDs: Constantin Radke, Thorsten Grehl, Philip van Damme
20 affiliations
  1. Department of Neurology, University Hospital Ulm, 89081 Ulm, Germany
  2. Center for Rare Diseases (ZSE) Ulm, Ulm University Hospital Center for Rare Diseases, 89081 Ulm, Germany
  3. German Center for Neurodegenerative Diseases (DZNE), Ulm site, 89081 Ulm, Germany
  4. Institute of Anatomy and Cell Biology, Ulm University School of Medicine, 89081 Ulm, Germany
  5. Department of Neurosciences, Laboratory of Neurobiology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000 Leuven, Belgium
  6. VIB, Center for Brain & Disease Research, 3001 Leuven, Belgium
  7. Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany
  8. Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, 86159 Augsburg, Germany
  9. Institute of Molecular Oncology and Stem Cell Biology (IMOS), Ulm University Hospital, 89081 Ulm, Germany
  10. Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA
  11. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA
  12. Department of Neurology, Centre for ALS and Other Motor Neuron Disorders, Alfried Krupp Krankenhaus Rüttenscheid, 45131 Essen, Germany
  13. Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
  14. Core Facility Organoids, Ulm University, 89081 Ulm, Germany
  15. Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands
  16. Division of Interdisciplinary Pancreatology, Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
  17. Unit for Single-Cell Genomics, Medical Faculty, Ulm University, 89081 Ulm, Germany
  18. Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden
  19. Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium
  20. Institute of Neuroanatomy, University Clinic RWTH Aachen, Wendlingweg 2, 52074 Aachen, Germany
Institutions: Universität Ulm (Germany); German Center for Neurodegenerative Diseases (Germany); University Hospital Ulm (Germany); VIB-KU Leuven Center for Brain & Disease Research (Belgium); KU Leuven (Belgium); Universitätsklinikum Aachen (Germany); RWTH Aachen University (Germany); University of Augsburg (Germany); Johns Hopkins University (United States); Johns Hopkins Medicine (United States); Alfried Krupp Hospital (Germany); Utrecht University (Netherlands); University Medical Center Utrecht (Netherlands); Umeå University (Sweden)
Journal: Acta neuropathologica communications, volume 14, issue 1, article 135
Dates: received 25 February 2026; accepted 11 June 2026; published online 25 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s40478-026-02351-6 · PMID 42351313 · PMCID PMC13307424 · OpenAlex W7165903645
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Connectivity
Keywords: NEK1, ALS, Genetics, Missense variant, Kinase, TDP-43 pathology, Autophagy
MeSH: Amyotrophic Lateral Sclerosis*, Mutation, Missense*, NIMA-Related Kinase 1*, Animals, Female, Humans, Male, Motor Neurons, Pedigree (* major topic)
Topic: Amyotrophic Lateral Sclerosis Research (Neurology, Medicine), according to OpenAlex
Funding: Universitätsklinikum RWTH Aachen
Citations: cited by 1 paper (Europe PMC); 31 references in the paper
Notices: A correction to this paper has been published (42477825, from Europe PMC)

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40478-026-02351-6.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The RNAseq source data have been uploaded to the ENA database with the identifier PRJEB98556.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 31 authors, 7 keywords, 9 MeSH terms, 1 funder, 31 references, 1 integrity notice.

Cite

This paper

Brenner, D., Ponomarenko, A., Petrut, I., Beyrle, S., Contardo, M., Loss, I., Radke, C., Frank, J., Zimmer, E., Schlesner, M., Achenbach, P., Scheveneels, W., Aly, A., Nazlican, H., Hesebeck-Brinkmann, J., Oeckl, P., Müller, K., Siebert, R., Böckers, T., . . . Catanese, A. (2026). A rare missense variant impacting NEK1 kinase function is associated with ALS. Acta neuropathologica communications, 14(1), 135. https://doi.org/10.1186/s40478-026-02351-6

BibTeX

@article{brenner2026rare,
author = {Brenner, David and Ponomarenko, Anna and Petrut, Iris and Beyrle, Sofia and Contardo, Matilde and Loss, Isabel and Radke, Constantin and Frank, Jonas and Zimmer, Eleni and Schlesner, Matthias and Achenbach, Pascal and Scheveneels, Wendy and Aly, Amr and Nazlican, Hülya and Hesebeck-Brinkmann, Jasper and Oeckl, Patrick and Müller, Kathrin and Siebert, Reiner and Böckers, Tobias and van Eijk, Kristel and Veldink, Jan and Kleger, Alexander and Mulaw, Medhanie and Andersen, Peter M and Forsberg, Karin and Weishaupt, Jochen H and Loghmani, Seyed Babak and Grehl, Thorsten and van Damme, Philip and Weis, Joachim and Catanese, Alberto},
title = {{A rare missense variant impacting NEK1 kinase function is associated with ALS}},
journal = {Acta neuropathologica communications},
year = {2026},
month = jun,
volume = {14},
number = {1},
pages = {135},
publisher = {BMC},
issn = {2051-5960},
doi = {10.1186/s40478-026-02351-6},
url = {https://doi.org/10.1186/s40478-026-02351-6},
pmid = {42351313},
pmcid = {PMC13307424}
}

RIS

TY - JOUR
AU - Brenner, David
AU - Ponomarenko, Anna
AU - Petrut, Iris
AU - Beyrle, Sofia
AU - Contardo, Matilde
AU - Loss, Isabel
AU - Radke, Constantin
AU - Frank, Jonas
AU - Zimmer, Eleni
AU - Schlesner, Matthias
AU - Achenbach, Pascal
AU - Scheveneels, Wendy
AU - Aly, Amr
AU - Nazlican, Hülya
AU - Hesebeck-Brinkmann, Jasper
AU - Oeckl, Patrick
AU - Müller, Kathrin
AU - Siebert, Reiner
AU - Böckers, Tobias
AU - van Eijk, Kristel
AU - Veldink, Jan
AU - Kleger, Alexander
AU - Mulaw, Medhanie
AU - Andersen, Peter M
AU - Forsberg, Karin
AU - Weishaupt, Jochen H
AU - Loghmani, Seyed Babak
AU - Grehl, Thorsten
AU - van Damme, Philip
AU - Weis, Joachim
AU - Catanese, Alberto
TI - A rare missense variant impacting NEK1 kinase function is associated with ALS
T2 - Acta neuropathologica communications
J2 - Acta Neuropathol Commun
PY - 2026
DA - 2026/06/25
VL - 14
IS - 1
SP - 135
SN - 2051-5960
PB - BMC
DO - 10.1186/s40478-026-02351-6
UR - https://doi.org/10.1186/s40478-026-02351-6
LA - en
ER -

CSL-JSON

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