Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features.
Genetic variation of the 16p11.2 deletion locus containing the gene and of is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of mutant ( ) 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 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 neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human variants suggests that variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.
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