ArticleiScience2020
An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3.
Article in iScience, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.Nature genetics · 2021Pooled it
- Nek1 defines a branch of centriolar microtubule length control parallel to CP110-Cep97.Nature communications · 2026Article
- Stress granule phase separation in stress-responsive cytosolic extract-in-oil droplets.Nature communications · 2026Article
- Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.Acta neurologica Belgica · 2026Review
- C21orf2 as a potential regulator of JAK2/STAT3 signaling in prostate cancer cell proliferation and apoptosis: an exploratory study.BMC cancer · 2026Article
- NEK Family Kinases: Structure, Function, and Role in Disease.Biomolecules · 2025Review
- Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS.iScience · 2025Article
- ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation.The EMBO journal · 2025Article
- Variants in CFAP410 cause a range of retinal and skeletal phenotypes.NPJ genomic medicine · 2025Article
- Review
- Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.Brain pathology (Zurich, Switzerland) · 2025Article
- ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.Acta neuropathologica communications · 2024Article
- Emerging Perspectives on Prime Editor Delivery to the Brain.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.Life science alliance · 2023Article
- Pathogenicity and functional analysis ofFrontiers in medicine · 2023Article
- Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy.Frontiers in neuroscience · 2023Review
- Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.Journal of neuromuscular diseases · 2023Article
- The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS.International journal of molecular sciences · 2022Review
- TTC30A and TTC30B Redundancy Protects IFT Complex B Integrity and Its Pivotal Role in Ciliogenesis.Genes · 2022Article
- Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.