CUL4B and X‑linked Intellectual Disability

CUL4B (HGNC:2555) has been robustly associated with X‑linked intellectual disability (MONDO:0100284). Multiple independent studies have documented pathogenic variants in CUL4B that co‐segregate with the disease phenotype in affected families, supporting its role in cognitive dysfunction and syndromic intellectual disability in males (PMID:20002452).

In several case reports and multi‑patient studies, affected males present with a characteristic constellation of features including intellectual disability, short stature, and additional neurological manifestations. Segregation analyses in these families demonstrate that the variants are inherited in an X‑linked manner, with affected males and carrier females displaying skewed X‑inactivation patterns (PMID:24898194).

Genetic evidence is underscored by the identification of multiple pathogenic alterations, including splice‐site and missense variants, confirmed in unrelated probands. For example, the variant c.1108C>T (p.Arg370Ter) has been repeatedly reported in patients, complementing the broader spectrum of CUL4B mutations observed across studies (PMID:17236139).

Functional studies further validate the disease mechanism by demonstrating that loss‐of‐function mutations in CUL4B disrupt the assembly and function of the CRL4 ubiquitin ligase complex. Experimental assessments in cellular models have shown that such mutations impair protein degradation pathways and neural progenitor cell proliferation, thereby providing mechanistic insight into the neurodevelopmental deficits observed in patients (PMID:17273978; PMID:22992378).

Integrating both genetic and functional data, the evidence supports a strong association between CUL4B and X‑linked intellectual disability. The convergence of segregation data, consistent mutation spectra (including the recurrent c.1108C>T (p.Arg370Ter) variant), and complementary functional assays emphasizes the clinical relevance for diagnostic evaluation and targeted testing in males with intellectual impairment.

Key Take‑home: The robust genetic and functional evidence substantiates the role of CUL4B mutations in X‑linked intellectual disability, underscoring its utility as a diagnostic marker and a target for future therapeutic strategies.

References

• Clinical Genetics • 2010 • A novel nonsense mutation in CUL4B gene in three brothers with X‑linked mental retardation syndrome PMID:20002452
• American Journal of Medical Genetics. Part A • 2014 • Donor splice‑site mutation in CUL4B is likely cause of X‑linked intellectual disability PMID:24898194
• American Journal of Human Genetics • 2007 • Mutations in CUL4B cause an X‑linked mental retardation syndrome PMID:17236139
• American Journal of Human Genetics • 2007 • Mutation in CUL4B, which encodes a member of cullin‑RING ubiquitin ligase complex, causes X‑linked mental retardation PMID:17273978
• BMC Neuroscience • 2012 • Cul4B regulates neural progenitor cell growth PMID:22992378

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