CRBN – Autosomal Recessive Non-syndromic Intellectual Disability

CRBN encodes the substrate receptor of the Cullin-RING E3 ubiquitin ligase complex and has been implicated in autosomal recessive non-syndromic intellectual disability (ARNS-ID) through identification of biallelic pathogenic variants in multiple consanguineous families ([PMID:28143899]).

In a consanguineous Saudi family, a homozygous missense variant c.1171T>C (p.Cys391Arg) co-segregated with severe intellectual disability, seizures, and self-mutilating behaviour in five affected individuals, with complete absence in 200 ethnically matched controls ([PMID:28143899]).

A recurrent nonsense variant c.1255C>T (p.Arg419Ter) has been reported in at least one additional ARNS-ID family, resulting in a truncated protein lacking the C-terminal 24 amino acids, and segregating with a mild cognitive phenotype ([PMID:18414909]). Both alleles are absent or extremely rare in population databases.

Inheritance is autosomal recessive, with segregation including five affected relatives in the Saudi kindred and further cases carrying p.Arg419Ter. The variant spectrum comprises one recurrent loss-of-function allele and one missense allele mapping to the CULT domain of CRBN.

Functional assays demonstrate that the p.Arg419Ter mutant exhibits enhanced autoubiquitination and proteasomal degradation, and disrupts neuronal BK channel assembly and kinetics, implicating impaired channel regulation in pathogenesis ([PMID:23983124], [PMID:18414909]).

Crbn-knockout mouse and Drosophila models recapitulate cognitive deficits and reduced presynaptic glutamate release; treatment with BK channel blockers (paxilline, iberiotoxin) or proteasome inhibitors rescues synaptic function and cognitive performance ([PMID:29530986], [PMID:23983124]). Additional studies reveal failure of p.Arg419Ter to inhibit AMPK, leading to mTOR-dependent repression of protein synthesis relevant to synaptic plasticity ([PMID:24993823]).

Together, genetic and experimental data support a loss-of-function mechanism by which biallelic CRBN variants cause ARNS-ID. This association meets ClinGen criteria for Moderate clinical validity with robust functional concordance, providing a basis for molecular diagnosis and potential targeted therapies.

Key Take-home: CRBN biallelic loss-of-function variants cause autosomal recessive non-syndromic intellectual disability via BK channel dysregulation, offering avenues for personalized intervention.

References

• Journal of medical genetics • 2017 • A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family PMID:28143899
• Neurogenetics • 2008 • Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation PMID:18414909
• The Journal of biological chemistry • 2013 • A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition PMID:23983124
• The Journal of neuroscience • 2018 • Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel PMID:29530986
• The Journal of biological chemistry • 2014 • Functional effects of a pathogenic mutation in Cereblon (CRBN) on the regulation of protein synthesis via the AMPK-mTOR cascade PMID:24993823

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