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 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 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.

Case Report: A Novel PAX3 Mutation Associated With Waardenburg Syndrome Type 1

“…Splice variants frequently give rise to alternative splicing and affect protein coding. Consistent with the results, the mutations identified in Ehlers-Danlos-syndrome-related gene COL5A1 (Tuna et al, 2019;Angwin et al, 2020) and Kaufman-Oculocerebrofacial-syndrome-related gene UBE3B (Cheon et al, 2019;Ambrozkiewicz et al, 2020) also had a higher risk of disease. However, no results of the PAX3 mutation were available through the prediction tools.…”

The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc

“…Ube3b -/mice generated in this study died at approximately 3 weeks, likely due to frail teeth, malnutrition and/or muscle weakness. Because of these overt phenotypes in Ube3b -/also reported elsewhere very recently (Cheon et al, 2019), we decided to study the role of Ube3b in neurons using Ube3b f/f mice and mice with Emx1-Cre +/--driven conditional knockout of Ube3b, described below. This approach circumvents the syndromic phenotype of Ube3b -/-, which partially limits the identification of brain-specific and neuron-specific phenotypes, and prevent the analysis of mature brains.…”

Identification of the Potential Key Circular RNAs in Elderly Patients With Postoperative Cognitive Dysfunction

“…UBE3B was associated with speech ability and intelligence development (Cheon et al, 2019). Thus, one target gene involved in POCD might be regulated by several circRNAs through different mechanisms.…”