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Abundance and localization of human UBE3A protein isoforms.

ABSTRACT: Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype.

SUBMITTER: Sirois CL

PROVIDER: S-EPMC7645711 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Abundance and localization of human UBE3A protein isoforms.

Sirois Carissa L CL Bloom Judy E JE Fink James J JJ Gorka Dea D Keller Steffen S Germain Noelle D ND Levine Eric S ES Chamberlain Stormy J SJ

Human molecular genetics 20201101 18

Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem ce ...[more]

PMID: 32833011

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