CUL4B

Chr XXLR

cullin 4B

Also known as: CUL-4B, MRXHF2, MRXS15, MRXSC, SFM2

NCBI Gene: 8450 ENSG00000158290 UniProt: Q13620 OMIM: 300304

The encoded protein forms an E3 ubiquitin ligase complex that catalyzes polyubiquitination of specific protein substrates and is required for proteolysis of DNA replication regulators including chromatin licensing and DNA replication factor 1 and cyclin E. Loss-of-function mutations cause X-linked syndromic intellectual developmental disorder, Cabezas type, with X-linked recessive inheritance. The gene is extremely intolerant to loss-of-function variation, consistent with its essential role in protein degradation pathways critical for DNA replication.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.091 OMIM phenotype

Clinical Summary— CUL4B

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Gene-Disease Validity (ClinGen)

X-linked intellectual disability, Cabezas type · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.48

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.77Z-score

OE missense 0.40 (0.35–0.47)

126 obs / 314.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.40 (0.35–0.47)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 0 / 35.0Missense obs/exp: 126 / 314.1Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCUL4B-related syndromic intellectual developmental disorder, Cabezas typeLOFXLR

This gene — mechanism propensity

0.3594th %ile

GOF

0.3590th %ile

LOF

0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.09 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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