dSMAX-2

Genetic Context

HGNC-Approved Gene Symbol

UBA1

Gene Full Name

ubiquitin like modifier activating enzyme 1

HGNC Gene Alias(es)

GXP1, UBE1

Chromosome

Xp11.3

Zygosity of Responsible Variant

Hemizygous (Male)/Homozygous (Female)

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
High

Prediction:
The literature predicts a loss-of-function mechanism for dSMAX-2: UBA1 encodes the sole E1 enzyme that activates ubiquitin and charges the downstream E2 cascade, and the hypomorphic exon 15 missense alleles (p.Met539Ile, p.Ser547Gly) together with expression-lowering regulatory variants leave residual activity too low to sustain protein turnover in motor neurons. Hemizygous males carry that reduced-function copy as their only UBA1, and restored wild-type E1 is predicted to rescue. Somatic p.Met41 variants confined to the myeloid lineage instead cause VEXAS syndrome, an acquired inflammatory disease.

Rationale:
A hemizygous male expresses no wild-type E1 for a mutant subunit to interfere with, so interference is unavailable as a mechanism and the phenotype tracks residual enzyme activity alone. Because ubiquitin activation is essential to every cell, only partial-function alleles are compatible with survival, and the motor neuron is where falling conjugation capacity shows first.

ClinVar Pathogenic Variants

View UBA1 ClinVar Variants

GeneReviews®

dSMAX-2 GeneReviews®

dSMAX-2 OMIM Entry

dSMAX-2 OMIM

UBA1 OMIM Entry

UBA1 OMIM