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    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 variation may 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. © 2020 The Author(s).

    Citation

    Jon M Madison, Karen Duong, Ellen F Vieux, Namrata D Udeshi, Sumaiya Iqbal, Elise Requadt, Shaunt Fereshetian, Michael C Lewis, Antonio S Gomes, Kerry A Pierce, Randall J Platt, Feng Zhang, Arthur J Campbell, Dennis Lal, Florence F Wagner, Clary B Clish, Steven A Carr, Morgan Sheng, Edward M Scolnick, Jeffrey R Cottrell. Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features. iScience. 2021 Jan 22;24(1):101935


    PMID: 33409479

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