Madison Jon M, Duong Karen, Vieux Ellen F, Udeshi Namrata D, Iqbal Sumaiya, Requadt Elise, Fereshetian Shaunt, Lewis Michael C, Gomes Antonio S, Pierce Kerry A, Platt Randall J, Zhang Feng, Campbell Arthur J, Lal Dennis, Wagner Florence F, Clish Clary B, Carr Steven A, Sheng Morgan, Scolnick Edward M, Cottrell Jeffrey R
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
iScience. 2020 Dec 11;24(1):101935. doi: 10.1016/j.isci.2020.101935. eCollection 2021 Jan 22.
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.
包含该基因的16p11.2缺失位点的基因变异与自闭症有关。这种基因关联表明，CUL3-KCTD13泛素连接酶的底物可能参与疾病发病机制。对KCTD13突变型（KCTD13-/-）和野生型神经元泛素化组进行比较，确定腺苷酸琥珀酸合成酶（ADSS）是一种催化单磷酸腺苷（AMP）合成第一步的酶，为KCTD13连接酶的底物。在KCTD13-/-神经元中，ADSS下游代谢产物琥珀酰腺苷（S-Ado）水平升高。值得注意的是，在具有自闭症和癫痫表型的代谢紊乱疾病腺苷酸琥珀酸裂解酶缺乏症中，S-Ado水平也会升高。用ADSS抑制剂处理可降低KCTD13-/-神经元中升高的S-Ado水平。最后，对人类KCTD13变体的功能分析表明，KCTD13变异可能会改变ADSS的泛素化。这些数据表明，琥珀酰-AMP代谢产物在KCTD13-/-神经元中积累，这一观察结果可能对我们理解16p11.2缺失综合征有启示意义。
