ClinVar

In affected members of a large family with intellectual developmental disorder (MRT2; 607417) previously described by Higgins et al. (2000), Higgins et al. (2004) identified a homozygous 1274C-T transition in exon 11 of the CRBN gene, resulting in an arg419-to-ter (R419X) substitution. The mutation was not detected in 400 control chromosomes. The truncation spares the Lon domain, but disrupts an N-myristoylation site and deletes a casein kinase-2 phosphorylation site at the C terminus, which may prevent proper subcellular targeting. As human Lon-containing proteins are localized to the mitochondria, where they selectively degrade short-lived polypeptides, Higgins et al. (2004) hypothesized that a defect in the CRBN gene may perturb nuclear regulation of mitochondrial energy metabolism.

Using RT-PCR to examine CRBN expression in lymphoblastoid cells derived from patients with the R419X mutation, Higgins et al. (2008) found that R419X-mutant CRBN was expressed at levels similar to wildtype protein. However, presence of the mutant CRBN resulted in significantly different expression of different KCNMA1 (600150) channel isoforms. Mutant CRBN protein was associated with persistent postnatal expression of the KCNMA1 isoform containing a site-2 insert that is usually downregulated in adult life. Persistence of protein isoforms with the site-2 insert would result in BK channels with higher intracellular calcium sensitivity, faster activation, and slower deactivation kinetics compared to the mature isoform without the site-2 insert. Higgins et al. (2008) postulated that such alterations could contribute to abnormal cortical development and cognitive impairments in patients with the mutation. The authors noted that R419X-mutant CRBN escapes nonsense-mediated decay.

Xu et al. (2013) reported that the R419X truncation occurred within the C-terminal thalidomide-binding region of CRBN. The mutation did not alter expression or localization of CRBN or formation of the CRBN-CRL4 E3 ligase complex, and it had no effect on ubiquitination of CRL4 E3 ligase target proteins. However, Xu et al. (2013) discovered that the C terminus of CRBN functioned as a ubiquitin autoinhibitory domain. C-terminal truncation in the R419X mutant permitted CRL4 E3 ligase-mediated ubiquitination of C-terminal lysines in CRBN with lys48-linked polyubiquitin chains, reducing the half-life of mutant CRBN compared with wildtype CRBN.