A missense mutation in theCRBNgene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family

Abstract

BackgroundAutosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning.ObjectivesWe aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members.MethodsClinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members.ResultsA missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site.ConclusionsThese findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype–phenotype correlations between CRBN mutations and the aetiology of ARNS-ID.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

“…We note that zebrafish and chicken both contain an Ile in the V388 position; however, these were reported to exhibit defects to limb/fin formation upon exposure to thalidomide or knock-down of Crbn ( Eichner et al, 2016 ; Ito et al, 2010 ), partially resembling thalidomide-induced defects. These findings are in contrast with the observations in higher eukaryotes, as Crbn knock-out mice have been reported to exhibit normal morphology ( Lee et al, 2013 ), and children harboring a homozygous C391R mutation in CRBN (C391 is a structural cysteine coordinating the zinc in the thalidomide-binding domain of CRBN and we failed to produce any protein from a C391R cDNA), a loss of function mutation, were born without characteristic birth defects but exhibited severe neurological defects ( Sheereen et al, 2017 ). Whether the phenotypes in zebrafish and chicken are a result of species-specific downstream pathways or the high dose (400 µM) and direct application of thalidomide to the limb buds ( Ito et al, 2010 ), which both could result in off-target effects, remains to be shown.…”

Cereblon attenuates DNA damage-induced apoptosis by regulating the transcription-independent function of p53

“…3e) while IMiDs interact with CRBN C terminus 19 and the fact that IMiDs do not regulate the ubiquitination of a protein, which interacts with the CRBN N terminus 43 . Although two CRBN mutants C391R and R419X cause different degree of intellectual disability 33,35 , these mutations did not affect the interaction between CRBN and p53 (Supplementary Figure S5), presumably because the mutated region is far away from p53-binding domain. This result suggests that the learning and memory deficits in those patients might not be closely linked to the p53 functions.…”

“…Furthermore, CRBN exhibits non-enzymatic functions independent to its associated E3 ligase in multiple processes, such as on epigenetic regulation of potassium voltage-gated channel subfamily A member 3 ( Kcna3 ) 30 , formation of sequestosome-1/p62 bodies 31 , and inhibition of ubiquitination of tumor necrosis factor receptor-associated factor 6 and TAK1-binding protein 2 32 through its interaction with DNA or proteins. In addition, two CRBN mutants C391R (Cys to Arg mutation at position 391) and R419X (Arg to stop codon mutation at position 419) have been discovered to be the genetic causes for different degree of intellectual disability, indicating the important roles of CRBN in the regulation of neuronal functions 33–35 . Moreover, it has also been discovered that CRBN protects neuronal cells from death induced by pathogenic protein aggregates in neurodegenerative diseases 31 .…”

CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

“…A nonsense mutation in CRBN with a premature stop at amino acid 419, CRBN R419X , was identified in a large kindred to cause non-syndromic ID [ 23 ]. Recently, another missense variant in the CRBN, CRBN C391R , was identified in five individuals with severe ID from a consanguineous family [ 24 ]. By immunoprecipitaion assays, we found that both CRBN R419X and CRBN C391R associated very weakly with DDB1 ( Fig 3C ).…”

“…Inactivation of BK channel by transcriptional silencing of the Fmr1 gene causes the most common inheritable ID, known as Fragile X syndrome (FXS) [ 21 , 22 ]. Autosomal recessive CRBN mutations have also been identified in ID patients in two unrelated families [ 23 , 24 ]. Genetic deletion of Slo1 [ 25 ] or Crbn [ 26 ] in mouse brain leads to impaired spatial learning or conditioned fear memory, respectively.…”