Journal Article

DZNE-2026-00684

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A rare missense variant impacting NEK1 kinase function is associated with ALS.

Brenner, D. (First author)DZNE* ; 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.DZNE* ; Müller, K. ; Siebert, R. ; Böckers, T.DZNE* ; van Eijk, K. ; Veldink, J. ; Kleger, A. ; Mulaw, M. ; Andersen, P. M. ; Forsberg, K. ; Weishaupt, J. H.DZNE* ; Loghmani, S. B. ; Grehl, T. ; van Damme, P. ; Weis, J. ; Catanese, A. (Last author)DZNE*

2026
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-026-02351-6

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.

Keyword(s): NIMA-Related Kinase 1: genetics (MeSH) ; NIMA-Related Kinase 1: metabolism (MeSH) ; Humans (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Mutation, Missense: genetics (MeSH) ; Female (MeSH) ; Motor Neurons: pathology (MeSH) ; Motor Neurons: metabolism (MeSH) ; Male (MeSH) ; Pedigree (MeSH) ; Animals (MeSH) ; ALS ; Autophagy ; Genetics ; Kinase ; Missense variant ; NEK1 ; TDP-43 pathology ; NIMA-Related Kinase 1 ; NEK1 protein, human

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Contributing Institute(s):

1. Translational Protein Biochemistry (AG Böckers)
2. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))
3. Translational Mass Spectrometry and Biomarker Research (AG Öckl)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Brenner, D. (First author)DZNE* ; 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.DZNE* ; Müller, K. ; Siebert, R. ; Böckers, T.DZNE* ; van Eijk, K. ; Veldink, J. ; Kleger, A. ; Mulaw, M. ; Andersen, P. M. ; Forsberg, K. ; Weishaupt, J. H.DZNE* ; Loghmani, S. B. ; Grehl, T. ; van Damme, P. ; Weis, J. ; Catanese, A. (Last author)DZNE*
Correction: A rare missense variant impacting NEK1 kinase function is associated with ALS.
Acta Neuropathologica Communications 14(1), 153 (2026) [10.1186/s40478-026-02380-1]2026   Files BibTeX | EndNote: XML, Text | RIS

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