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<p>Heterozygous truncating loss-of-function (LoF) variants in <i>NEK1</i> are a known cause of amyotrophic lateral sclerosis (ALS). <i>NEK1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • 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

摘要

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.