A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition

Xu, Guoqiang; Jiang, Xiaogang; Jaffrey, Samie R.

doi:10.1074/jbc.m113.472092

Cited by 41 publications

(38 citation statements)

References 45 publications

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“…The severe ID, intractable seizures and self-mutilating behaviour observed in the proband and other affected family members might have resulted from a loss of structural stability of the CRBN protein when a cysteine residue at a conserved site is replaced by an arginine residue. Moreover, Xu et al 16 have proposed that amino acid residues, 339-418, in the CRBN protein form a major ubiquitylation domain as shown in figure 2B. We therefore deduce that the mutation p. Cys391Arg reported in this Saudi family disrupts this ubiquitylation site.…”

Section: Discussionsupporting

confidence: 49%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 49%

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

et al. 2017

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“…Finally, a homozygous LOF allele was identified in UBQLN , which has been studied in Alzheimer disease due to its potential role in proteasome degradation and its interaction with PSEN1 and PSEN2 (Bertram et al, 2005; Bird, 2005; Stieren et al, 2011). The ubiquitin-proteasome system has recently been proposed to play a role in the pathogenesis of Down syndrome (Granese et al, 2013), and several members of this pathway have been implicated in intellectual disability ( UBE2A, UBE3B, CRBN ) (Basel-Vanagaite et al, 2012; Nascimento et al, 2006; Xu et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease

Karaca

Harel

Pehlivan

et al. 2015

Neuron

271

319

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Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families, and homozygous loss of function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

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“…HA-CRBN R419X (human) and HA-Crbn R422X (mouse) were constructed as described in the previous report (22). Cells were transfected using Lipofectamine TM LTX (Invitrogen), and then cells were seeded 24 h before lysate preparation.…”

Section: Methodsmentioning

confidence: 99%

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Lee

Yang

Choi

et al. 2014

Journal of Biological Chemistry

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Background: Deficiency or nonsense mutation of CRBN causes memory deficits. Results: Truncated CRBN has insufficient affinity for AMPK␣ and cannot modulate the AMPK-mTOR pathway. Conclusion: CRBN modulates protein synthesis through the AMPK-mTOR pathway, and may be critical for certain forms of memory encoding. Significance: Our findings suggest the first plausible mechanism for the phenotype resulting from the CRBN mutation.

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A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition

Cited by 41 publications

References 45 publications

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

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

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

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