MUS81

Chr 11

MUS81 structure-specific endonuclease subunit

Also known as: SLX3

NCBI Gene: 80198 ENSG00000172732 UniProt: Q96NY9

This gene encodes a structure-specific endonuclease that forms heterodimeric complexes with EME1 or EME2 proteins to resolve DNA recombination intermediates, process stalled replication forks, and maintain genome stability through cleavage of specific DNA structures including Holliday junctions and DNA flaps. Biallelic mutations cause a severe neurodevelopmental disorder with intellectual disability, microcephaly, growth retardation, and distinctive facial features, with symptoms apparent from early infancy. The gene shows extreme intolerance to loss-of-function variants (pLI near 1.0), indicating that even heterozygous loss-of-function mutations are likely pathogenic, and inheritance can be either autosomal dominant or autosomal recessive depending on the specific variant.

ResearchSummary from RefSeq, UniProt

This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.99

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.62

OE 0.70 (0.51–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.06Z-score

OE missense 0.99 (0.91–1.09)

331 obs / 333.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.51–0.99)

0≤0.351.4

Missense OE?0.99 (0.91–1.09)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 24 / 34.2Missense obs/exp: 331 / 333.9Syn Z: 0.43

Background carrier burden — how many people carry a rare variant somewhere in MUS81?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 66

856 rare PASS variants

Rare truncating (LoF)

1 in 660

183 rare PASS variants

Rare synonymous (reference)

1 in 250

340 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MUS81. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 99	1 in 800
South Asian	~43k	1 in 68	1 in 740
Remaining (unassigned)	~30k	1 in 58	1 in 480
European (Finnish)	~27k	1 in 160	1 in 1,400
Admixed American	~22k	1 in 76	1 in 670
African / African American	~21k	1 in 54	1 in 200
East Asian	~20k	1 in 51	1 in 390
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 63	1 in 480

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓