Mutation Update for UBE3A Variants in Angelman Syndrome

Abstract

Angelman syndrome is a neurodevelopmental disorder caused by a deficiency of the imprinted and maternally expressed UBE3A gene. Although de novo genetic and epigenetic imprinting defects of UBE3A genomic locus account for majority of Angelman diagnoses, approximately 10% of individuals affected with Angelman syndrome are a result of UBE3A loss-of-function mutations occurring on the expressed maternal chromosome. The variants described in this manuscript represent the analysis of 2,515 patients referred for UBE3A gene sequencing at our institution, along with a comprehensive review of the UBE3A mutation literature. Of these, 267 (10.62%) patients had a report issued for detection of a UBE3A gene nucleotide variant, which in many cases involved family studies resulting in reclassification of variants of unknown clinical significance (VUS). Overall, 111 (4.41%) probands had a nucleotide change classified as pathogenic or strongly favored to be pathogenic, 29 (1.15%) had a VUS, and 126 (5.0%) had a nucleotide change classified as benign or strongly favored to be benign. All variants and their clinical interpretations are submitted to NCBI ClinVar, a freely accessible human variation and phenotype database.

An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

“…Most cases of AS arise due to a deletion of the maternal copy of UBE3A , but some AS patients (~10%) harbor missense mutations in the coding region of UBE3A (Sadikovic et al, 2014). Some of these AS-linked mutations cluster near the catalytic cysteine (C820) and disrupt the ubiquitin ligase activity of UBE3A (Sadikovic et al, 2014).…”

“…Some of these AS-linked mutations cluster near the catalytic cysteine (C820) and disrupt the ubiquitin ligase activity of UBE3A (Sadikovic et al, 2014). However, the majority of these mutations are located far from the catalytic site.…”

“…Two of these mutations (R39H, A178T) are now recognized as benign variants and are not associated with AS (Malzac et al, 1998; Sadikovic et al, 2014). The E550L mutant does not effectively target the UBE3A substrate HHR23A for ubiquitination (Cooper et al, 2004), but how the I329T mutation affects UBE3A function is unknown (Camprubi et al, 2009).…”

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

“…Point mutations in the maternal copy occur throughout the UBE3A gene (Figure 2). Frameshift mutations are the most abundant and concentrated in the HECT domain, but nonsense, missense, and other types of mutations are dispersed throughout the gene [48, 49]. …”

“…Alternatively spliced exons 1–8 are shown in dark grey, consistent exons are in light grey, and alternative exons due to polyadenylation differences are hatched grey. Current numbering of exons was according to [48]. …”