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ADHD Attention Deficit and Hyperactivity Disorders

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01.03.2019 | Original Article

Effect of disease-associated SLC9A9 mutations on protein–protein interaction networks: implications for molecular mechanisms for ADHD and autism

verfasst von: Yanli Zhang-James, Marc Vaudel, Olav Mjaavatten, Frode S. Berven, Jan Haavik, Stephen V. Faraone

Erschienen in: ADHD Attention Deficit and Hyperactivity Disorders | Ausgabe 1/2019

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Abstract

Na⁺/H⁺ Exchanger 9 (NHE9) is an endosomal membrane protein encoded by the Solute Carrier 9A, member 9 gene (SLC9A9). SLC9A9 has been implicated in attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), epilepsy, multiple sclerosis and cancers. To better understand the function of NHE9 and the effects of disease-associated variants on protein–protein interactions, we conducted a quantitative analysis of the NHE9 interactome using co-immunoprecipitation and isobaric labeling-based quantitative mass spectrometry. We identified 100 proteins that interact with NHE9. These proteins were enriched in known functional pathways for NHE9: the endocytosis, protein ubiquitination and phagosome pathways, as well as some novel pathways including oxidative stress, mitochondrial dysfunction, mTOR signaling, cell death and RNA processing pathways. An ADHD-associated mutation (A409P) significantly altered NHE9’s interactions with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling. An ASD nonsense mutation in SLC9A9, R423X, produced no-detectable amount of NHE9, suggesting the overall loss of NHE9 functional networks. In addition, seven of the NHE9 interactors are products of known autism candidate genes (Simons Foundation Autism Research Initiative, SFARI Gene) and 90% of the NHE9 interactome overlap with SFARI protein interaction network PIN (p < 0.0001), supporting the role of NHE9 interactome in ASDs molecular mechanisms. Our results provide a detailed understanding of the functions of protein NHE9 and its disrupted interactions, possibly underlying ADHD and ASDs. Furthermore, our methodological framework proved useful for functional characterization of disease-associated genetic variants and suggestion of druggable targets.

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Titel: Effect of disease-associated SLC9A9 mutations on protein–protein interaction networks: implications for molecular mechanisms for ADHD and autism
verfasst von: Yanli Zhang-James
Marc Vaudel
Olav Mjaavatten
Frode S. Berven
Jan Haavik
Stephen V. Faraone
Publikationsdatum: 01.03.2019
Verlag: Springer Vienna
Erschienen in: ADHD Attention Deficit and Hyperactivity Disorders / Ausgabe 1/2019
Print ISSN: 1866-6116
Elektronische ISSN: 1866-6647
DOI: https://doi.org/10.1007/s12402-018-0281-x

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Effect of disease-associated SLC9A9 mutations on protein–protein interaction networks: implications for molecular mechanisms for ADHD and autism

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