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

iScience (Jan 2021)

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

Affiliations

Jon M. Madison: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Karen Duong: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ellen F. Vieux: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Namrata D. Udeshi: Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Sumaiya Iqbal: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Elise Requadt: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Shaunt Fereshetian: Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Michael C. Lewis: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Antonio S. Gomes: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Kerry A. Pierce: Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Randall J. Platt: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Feng Zhang: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Arthur J. Campbell: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Dennis Lal: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Florence F. Wagner: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Clary B. Clish: Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Steven A. Carr: Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Morgan Sheng: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Edward M. Scolnick: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Jeffrey R. Cottrell: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

Journal volume & issue: Vol. 24, no. 1
p. 101935

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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