The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK

Proceedings of the National Academy of Sciences of the United States of America
Solmi CheonMaria Chahrour

Abstract

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b-/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b-/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b-/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b-/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma fr...Continue Reading

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Citations

Oct 4, 2019·JCI Insight·Travis B LearBill B Chen
Feb 14, 2021·Molecular and Cellular Neurosciences·Hiroshi Kawabe, Judith Stegmüller
Feb 20, 2021·Pharmacology & Therapeutics·Sunil SinghJ Sivaraman
Mar 23, 2021·Frontiers in Genetics·Qiuming HuHaoyu Li
Aug 7, 2021·Frontiers in Physiology·Gagandeep MannOlasunkanmi A J Adegoke
Oct 3, 2021·Journal of Molecular Biology·Olga Levin-KravetsGali Prag

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