Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features

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

doi:10.1016/j.isci.2020.101935

Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features

iScience. 2020 Dec 11;24(1):101935. doi: 10.1016/j.isci.2020.101935. eCollection 2021 Jan 22.

Authors

Jon M Madison¹, Karen Duong¹, Ellen F Vieux¹, Namrata D Udeshi², Sumaiya Iqbal^{1

3}, Elise Requadt¹, Shaunt Fereshetian², Michael C Lewis¹, Antonio S Gomes¹, Kerry A Pierce⁴, Randall J Platt^{1

5}, Feng Zhang^{1

5}, Arthur J Campbell^{1

3}, Dennis Lal^{1

6}, Florence F Wagner^{1

3}, Clary B Clish⁴, Steven A Carr², Morgan Sheng¹, Edward M Scolnick¹, Jeffrey R Cottrell¹

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ McGovern Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

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 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.

Keywords: Metabolomics; Molecular Neuroscience; Proteomics.