Abstract
The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.
Highlights
The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood
We utilized the luciferase-based β-catenin activity reporter (BAR)[20], which is activated in a dose-dependent way by UBE3A (Fig. 1c), to determine if it can accurately assess the activity of UBE3A variants
We found that hyperactivating mutations segregate with affected phenotypes in two unrelated families, and consistent with the neuronal imprinting of UBE3A, our mouse modeling and patient data both strongly suggest that hyperactivating mutations confer an increased risk for pathogenicity when present on the maternallyinherited allele
Summary
The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. This method has been effective in establishing causality, a simple loss-of-function model is insufficient to account for the broad phenotypic heterogeneity observed in many neurodevelopmental disorders This is especially important for the millions of uncharacterized coding variants identified in the human genome[1,2], some of which represent pathogenic mutations that may bi-directionally alter the functional valence of a protein (loss or gain-of-function). There are only two known examples that link UBE3A gain-offunction to neurodevelopmental disease This includes one de novo hyperactivating missense mutation identified in a child with autism[12,13], and a microduplication of UBE3A that segregates with neuropsychiatric phenotypes in one family[14]. Our results provide strong evidence that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggest that detailed functional variant analysis can provide a widely-applicable method to identify mechanistic sub-classes of genetic disorders
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