Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features
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2021-01
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Journal Article
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Abstract
Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13(-/-)) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13(-/-) neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13(-/-)neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variationmay alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13(-/-) neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.
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24 (1)
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101935
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Cell Press
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09580 - Platt, Randall / Platt, Randall