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

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 <i>UBE3B</i>, but the underlying biological mechanisms are completely unknown. We found that loss of <i>Ube3b</i> in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of <i>Ube3b</i>^-/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. <i>Ube3b</i>^-/- 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 <i>Ube3b</i>^-/- 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 <i>Ube3b</i>^-/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous <i>UBE3B</i> mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.