ArticleAmerican journal of human genetics2016
Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 113 citations in OpenAlex.
- Ufl1-Mediated UFMylation Sustains Amelogenesis by Stabilizing RUNX2.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining.Nature communications · 2026Article
- The mechanistic basis and cellular functions of UFMylation.Nature reviews. Molecular cell biology · 2026Review
- Autobehaver: An AI-Based Pipeline for Animal Behavior Analysis.bioRxiv : the preprint server for biology · 2026Article
- Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.Nature communications · 2026Article
- A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3.Acta neuropathologica · 2026Article
- Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function.EMBO molecular medicine · 2026Article
- The UFM1 Conjugation System: A Master Regulator of Cellular Stress Surveillance in Human Disease.Biology · 2026Review
- UBA5 deficiency disrupts mitochondrial autophagy via the PINK1-parkin pathway and impairs myoblast proliferation.Biological research · 2026Article
- UFM1 at the endoplasmic reticulum: linking ER stress, ribosome quality control, and ER-phagy.Essays in biochemistry · 2025Review
- MCM5 UFMylation regulates replication origin firing and fork progression.The EMBO journal · 2025Article
- Ufmylation Suppresses Unfolded Protein Response to Prevent Peripartum Cardiomyopathy.JACC. Basic to translational science · 2025Article
- UFMylation System: Biological Functions, Molecular Mechanisms, Diseases, and Drug Discovery.MedComm · 2025Review
- Studies on the functional role of UFMylation in cells (Review).Molecular medicine reports · 2025Review
- The many connections of UFMylation with Alzheimer's disease: a comprehensive review.Molecular neurodegeneration · 2025Review
- Neuronal CDK5RAP3 deficiency leads to encephalo-dysplasia via upregulation of N-glycosylases and glycogen deposition.Cell death discovery · 2025Article
- Multifaceted roles of UFMylation in health and disease.Acta pharmacologica Sinica · 2025Review
- UFL1 promotes survival and function of virtual memory CD8 T cells.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Hypomyelinating Leukodystrophy 14 (HLD14)-Related UFC1 p.Arg23Gln Decreases Cell Morphogenesis: A Phenotype Reversable with Hesperetin.Medicines (Basel, Switzerland) · 2025Article
- UFMylation: A Potential Modification for Neurological Diseases.Current neuropharmacology · 2025Review
9 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 10 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.
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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.