Alt. symbols: A1S9T | GXP1 | UBE1 | UBE1X | POC20 | CFAP124

Approved name: ubiquitin like modifier activating enzyme 1
Alt. names: ubiquitin-activating enzyme E1 (A1S9T and BN75 temperature sensitivity complementing), ubiquitin-activating enzyme E1, ubiquitin-like modifier activating enzyme 1 | UBA1, ubiquitin-activating enzyme E1 homolog (yeast), POC20 centriolar protein homolog (Chlamydomonas)

Location: Xp11.3: 47190861 - 47215128 (+)
Gene type: protein_coding, 9 transcripts.

Scores: LoFtool: 0.342000 | pLI: 0.99999074 | LOEUF: 0.108

HGNC: 12469

NCBI: 7317, RefSeq: NG_009161.1

Ensembl: ENSG00000130985.17

LRG_ | Status: none

OMIM: 314370

Expression | ProteinAtlas

UBA1 encodes a ubiquitin activating enzyme (E1) that catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system (PMID: 1606621, 1447181, 33108101). It has been shown essential for the formation of radiation-induced foci, timely DNA repair and for replication stress responses by promoting TP53BP1 and BRCA1 recruitment to sites of DNA damage (PMID: 22456334).

Germline UBA1 loss-of-function (LOF) is associated with X-linked spinal muscular atrophy-2 (SMAX2) [OMIM: 301830], characterized by neonatal onset severe hypotonia, areflexia, and multiple congenital contractures due to loss of anterior horn cells (PMID: 18179898). De novo somatic UBA1 mutations are associated with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [OMIM: 301054], an adult-onset inflammatory condition characterized by recurrent fevers, lung and skin inflam mation, vasculitis, deep vein thrombosis, arthralgias, and ear and nose chondritis. Though predominantly seen in older males, affected females have been described, due to either germline or age-dependent acquired monosomy X (PMID: 33789873, 33930131, 34077651, 34802542, 34911285). Laboratory studies show elevated inflammatory markers, variable autoantibody production, hematologic abnormalities such as macrocytic anemia, and bone marrow pathology showing myeloid and erythroid precursors with degenerative vacuolization and variable hematopoietic dyspoiesis and dysplasias (PMID: 33108101, 34489099, 34802541). By current estimates, three somatic missense changes in codon p.Met41 of exon 3 account for over 92% of all VEXAS cases though more mutations are still being identified (PMID: 34802542). These affect transcriptional initiation of the cytoplasmic UBA1 isoform (UBA1b), which uses p.Met41 as its start codon, resulting in production of a novel isoform (UBA1c) with reduced function that uses alternative start codon p.Met67. This results in a global loss of ubiquitination and activation of innate immune pathways and the unfolded protein response (PMID: 33108101). The next most common mutations are those affecting the canonical splice acceptor site of exon 3, which also leads to a loss of UBA1b, mimicking the effect of the Met41 substitution mutations. In contrast to the 2 groups of mutations mentioned above, the p.Ser56Phe mutation in exon 3 does not promote UBA1b loss or UBA1c production, but instead causes a temperature dependent reduction in UBA1 ubiquitination activity (PMID: 33690815). [Load More]