| First Author | Madison JM | Year | 2021 |
| Journal | iScience | Volume | 24 |
| Issue | 1 | Pages | 101935 |
| PubMed ID | 33409479 | Mgi Jnum | J:311524 |
| Mgi Id | MGI:6718092 | Doi | 10.1016/j.isci.2020.101935 |
| Citation | Madison JM, et al. (2021) Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features. iScience 24(1):101935 |
| abstractText | 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. |
