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Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3662-3667. doi: 10.1073/pnas.1818751116. Epub 2019 Feb 11.

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

Author information

1
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
GeneDx Inc., Gaithersburg, MD 20877.
4
Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
5
Division of Human Genetics and the Metabolic Disease Program, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
6
Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
7
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
8
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; maria.chahrour@utsouthwestern.edu.
9
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390.

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.

KEYWORDS:

BCKDK; UBE3B; autism spectrum disorder; intellectual disability; ubiquitination

PMID:
30808755
PMCID:
PMC6397573
DOI:
10.1073/pnas.1818751116
[Indexed for MEDLINE]
Free PMC Article

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