MassIVE MSV000085846

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Regulation of AMP synthesis by a KCTD13 ubiquitin ligase connects 16p11.2 deletion syndrome to a metabolic disorder with autistic features

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Description

Madison JM, Duong K, Vieux EF, Iqbal S, Requadt E, Udeshi ND, Fereshetian S, Lewis MC, Gomes AS, Pierce KA, Platt RJ, Zhang F, Campbell AJ, Lal D, Wagner FF, Clish CB, Carr SA, Scolnick EM, Cottrell JR. 2020. Genetic variation of KCTD13 at the 16p11.2 deletion locus and of CUL3 are linked with autism, suggesting that substrates of a CUL3-KCTD13 ubiquitin ligase complex may be involved in disease pathogenesis. By comparing neuronal ubiquitylomes of Kctd13 mutant (Kctd13-delta) and wild-type mouse neurons, we identified a novel substrate of the KCTD13 ligase: adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in AMP synthesis. We found increased ADSS levels in Kctd13-delta neurons, as well as increased levels of succinyl-adenosine (S-Ado), a purine metabolite downstream of ADSS. Intriguingly, elevated S-Ado levels are the hallmark of adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. Importantly, these increased S-Ado levels in Kctd13-delta neurons were restored by treatment with an ADSS inhibitor. Lastly, analysis and functionalization of human KCTD13 variants suggests that KCTD13 variation may contribute to altered ubiquitination of ADSS and dysregulation of purine metabolism. Our results suggest that accumulation of succinyl-AMP metabolites may contribute to autistic features of the 16p11.2 deletion syndrome and that reducing ADSS activity may be therapeutically beneficial for these patients. [doi:10.25345/C5ZJ13] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: SILAC

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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