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

Abstract

KCTD13 deletion leads to decreases in ubiquitination and increases in levels of ADSS KCTD13 deletion increases S-Ado levels, a metabolite observed in ADSL deficiency Treatment of KCTD13 deletion neurons with an ADSS inhibitor reduces S-Ado levels Human KCTD13 variants can alter ubiquitination of ADSS

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

“…Clinical studies have found mitochondrial and metabolic dysfunction or changes in metabolites in primary lymphocytes or brain tissue in individuals with ASD, but whether this is direct or indirect is not known (Anitha et al, 2012; Frye and Rossignol, 2011; Frye et al, 2013; Kurochkin et al, 2019; Rose et al, 2014, 2018; Rossignol and Frye, 2012; Wang et al, 2016b). Some ASD-associated syndromic disorders, co-morbid disorders and genetic ASD models have shown deficits in mitochondrial and metabolic processes, however the specific proteins involved were unknown (Bülow et al, 2021; Ebrahimi-fakhari et al, 2016; Fernandez et al, 2019; Jagtap et al, 2019; Kanellopoulos et al, 2020; Li et al, 2019; Licznerski et al, 2020; Madison et al, 2021; Menzies et al, 2021; Shen et al, 2019b; Shulyakova et al, 2017). Our findings indicate that TCA cycle and mitochondrial activity proteins are interacting with multiple ASD-risk genes.…”

“…While, two ASD-risk genes (RHEB and BCKDK) have been previously implicated directly in metabolic processes 66, 106 . This highlights that our screen can identify relevant protein interactions and may even suggest a more direct connection between mitochondrial/metabolic processes and some genetic models (CDKL5 and KCTD13) 103, 105 .…”

“…A mouse model expressing an mtDNA variant was shown to display autism associated behavioral deficits 97 , but the variant is weakly associated with ASD. Some ASD associated syndromic disorders, co-morbid disorders and genetic ASD models have shown deficits in mitochondrial and metabolic processes, however the specific proteins involved were unknown 52–54, 98–104, 105 . Our findings indicate that TCA cycle and mitochondrial activity proteins are interacting with multiple ASD-risk genes, including genes that were not previously connected to metabolic processes.…”

Genomics 2 Proteins portal: A resource and discovery tool for linking genetic screening outputs to protein sequences and structures

“…Genetic screening is increasingly applied in clinical practice, leading to the identification of a rapidly growing number of genetic variations 47–49 . One of the challenges in modern biology is decoding the functional implications of these genetic variations at the molecular level 37,38,40,50–55 . This is pivotal not only for unraveling the disease mechanisms 39,56–59 but also for leveraging this knowledge to drive therapeutic developments 60–63 .…”

KCTD10 regulates brain development by destabilizing brain disorder–associated protein KCTD13

“…The KCTD (potassium channel tetramerization domain-containing) family consists of 25 soluble proteins that share a conserved N-terminal potassium (K + ) channel tetramerization domain (a BTB domain subtype) but have diverse C-termini. Many KCTD-encoding genes have been linked with neurodevelopmental and neuropsychiatric disorders, with varying degrees of genetic evidence implicating KCTD genes in neurocognitive disorders ( KCTD3 ) ( 8 – 10 ); progressive myoclonus epilepsy ( KCTD7 ) ( 11 – 19 ); bipolar disorder, depression, and schizophrenia (KCTD12) ( 20 – 22 ); autism and schizophrenia ( KCTD13 ) ( 23 – 26 ); movement disorders ( KCTD17 ) ( 27 – 30 ); epilepsy and autism ( KCTD18 ) ( 31 ); cerebral visual impairment ( KCTD19 ) ( 32 ); Alzheimer’s disease ( KCTD2 ) ( 33 ); and sporadic amyotrophic lateral sclerosis ( BTBD10 ) ( 34 ).…”