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

Solmi Cheon, Kiran Kaur, Nadine Nijem, Islam Oguz Tuncay, Pooja Kumar, Milan Dean, Jane Juusola, Maria J. Guillen-Sacoto, Emma Bedoukian, Lynne Ierardi-Curto, Paige Kaplan, G. Bradley Schaefer, Prashant Mishra, Maria Chahrour

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3662-3667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number9
DOIs
StatePublished - Feb 26 2019

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Keywords

  • Autism spectrum disorder
  • BCKDK
  • Intellectual disability
  • UBE3B
  • Ubiquitination

ASJC Scopus subject areas

  • General

Cite this

Cheon, S., Kaur, K., Nijem, N., Tuncay, I. O., Kumar, P., Dean, M., Juusola, J., Guillen-Sacoto, M. J., Bedoukian, E., Ierardi-Curto, L., Kaplan, P., Bradley Schaefer, G., Mishra, P., & Chahrour, M. (2019). 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, 116(9), 3662-3667. https://doi.org/10.1073/pnas.1818751116