dHMN1-UBE3C

Genetic Context

HGNC-Approved Gene Symbol

UBE3C

Gene Full Name

ubiquitin protein ligase E3C

HGNC Gene Alias(es)

KIAA0010

Chromosome

7q36.3

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Unknown

Details

Mechanistic basis:
Unresolved

Confidence:
Low

Prediction:
The literature does not resolve a mechanism for dHMN1-UBE3C. Cutrupi et al. (2023) traced the disease to a genomic insertion creating a UBE3C-intergenic fusion transcript, which splices duplicated UBE3C exons 1 to 10 onto a pseudo-exon. The transcript escapes nonsense-mediated decay, its product stops short of the HECT catalytic domain, and full-length UBE3C is reduced in patient motor neurons, but ubiquitin ligase activity itself was never measured.

Rationale:
Three readings fit the same observation and predict different mechanisms: the truncated product acting on the normal protein, transcriptional interference in cis at the duplicated locus, or a toxicity belonging to the fusion product, which is what expressing it in neurons produces. What the evidence does settle is the negative case, since biallelic UBE3C loss causes a separate recessive neurodevelopmental disease and its heterozygous carriers have no neuropathy, ruling out a simple halved dose.

ClinVar Pathogenic Variants

View UBE3C ClinVar Variants

UBE3C OMIM Entry

UBE3C OMIM