UBAP1

Chr 9AD

ubiquitin associated protein 1

Also known as: NAG20, SPG80, UAP, UBAP, UBAP-1

NCBI Gene: 51271 ENSG00000165006 UniProt: Q9NZ09 OMIM: 609787

The protein is a component of the ESCRT-I complex that binds ubiquitinated cargo proteins and regulates their sorting into multivesicular bodies and proteasomal degradation. Mutations cause spastic paraplegia 80 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 0.91, LOEUF = 0.38), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the UBA domain family, whose members include proteins having connections to ubiquitin and the ubiquitination pathway. The ubiquitin associated domain is thought to be a non-covalent ubiquitin binding domain consisting of a compact three helix bundle. This particular protein originates from a gene locus in a refined region on chromosome 9 undergoing loss of heterozygosity in nasopharyngeal carcinoma (NPC). Taking into account its cytogenetic location, this UBA domain family member is being studies as a putative target for mutation in nasopharyngeal carcinomas. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.381 OMIM phenotype

Clinical Summary— UBAP1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.912

Z-score 3.32

OE 0.12 (0.05–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.87Z-score

OE missense 0.85 (0.77–0.95)

240 obs / 281.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.38)

0≤0.351.4

Missense OE?0.85 (0.77–0.95)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 2 / 16.6Missense obs/exp: 240 / 281.0Syn Z: 0.11

This gene — mechanism propensity

0.4488th %ile

GOF

0.4875th %ile

LOF

0.62top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.38

DN1 literature citation

Literature Evidence

DNOur biochemical and cell biology evidence collectively points to a dominant-negative pathomechanism in which the truncated gene products from the disease alleles dysregulate endosomal processing and ubiquitinated protein sorting, thereby promoting neurodegeneration, potentially as mediated by apopto1

LOFWe identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80).2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References