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

  • Original Article
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ADHD Attention Deficit and Hyperactivity Disorders

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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References

  • Aasebo E, Opsahl JA, Bjorlykke Y, Myhr KM, Kroksveen AC, Berven FS (2014) Effects of blood contamination and the rostro-caudal gradient on the human cerebrospinal fluid proteome. PLoS ONE 9:e90429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adviento B, Corbin IL, Widjaja F, Desachy G, Enrique N, Rosser T, Risi S, Marco EJ, Hendren RL, Bearden CE, Rauen KA, Weiss LA (2014) Autism traits in the RASopathies. J Med Genet 51:10–20

    Article  CAS  PubMed  Google Scholar 

  • Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, Preiss R, Arulmani U, Widmer A, Gitton X, Kellner H (2011) Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord 12:153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antshel KM, Zhang-James Y, Faraone SV (2013) The comorbidity of ADHD and autism spectrum disorder. Expert Rev Neurother 13:1117–1128

    Article  CAS  PubMed  Google Scholar 

  • Assenov Y, Ramirez F, Schelhorn SE, Lengauer T, Albrecht M (2008) Computing topological parameters of biological networks. Bioinformatics 24:282–284

    Article  CAS  PubMed  Google Scholar 

  • Beggs JE, Tian S, Jones GG, Xie J, Iadevaia V, Jenei V, Thomas G, Proud CG (2015) The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding. Biochem J 467:63–76

    Article  CAS  PubMed  Google Scholar 

  • Ben-David E, Shifman S (2012) Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet 8:e1002556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertrand B, Wakabayashi S, Ikeda T, Pouyssegur J, Shigekawa M (1994) The Na+/H+ exchanger isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins. Identification and characterization of calmodulin-binding sites. J Biol Chem 269:13703–13709

    CAS  PubMed  Google Scholar 

  • Biederman J, Monuteaux MC, Faraone SV, Mick E (2009) Parsing the associations between prenatal exposure to nicotine and offspring psychopathology in a nonreferred sample. J Adolesc Health 45:142–148

    Article  PubMed  PubMed Central  Google Scholar 

  • Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Anney R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink M, Arnold R, Boer F, Buschgens C, Butler L, Christiansen H, Feldman L, Fleischman K, Fliers E, Howe-Forbes R, Goldfarb A, Heise A, Gabriels I, Korn-Lubetzki I, Johansson L, Marco R, Medad S, Minderaa R, Mulas F, Muller U, Mulligan A, Rabin K, Rommelse N, Sethna V, Sorohan J, Uebel H, Psychogiou L, Weeks A, Barrett R, Craig I, Banaschewski T, Sonuga-Barke E, Eisenberg J, Kuntsi J, Manor I, McGuffin P, Miranda A, Oades RD, Plomin R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Taylor E, Thompson M, Faraone SV, Asherson P (2006) The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11:934–953

    Article  CAS  PubMed  Google Scholar 

  • Bullis BL, Li X, Singh DN, Berthiaume LG, Fliegel L (2002) Properties of the Na+/H+ exchanger protein. Detergent-resistant aggregation and membrane microdistribution. Eur J Biochem 269:4887–4895

    Article  CAS  PubMed  Google Scholar 

  • Butland SL, Sanders SS, Schmidt ME, Riechers SP, Lin DT, Martin DD, Vaid K, Graham RK, Singaraja RR, Wanker EE, Conibear E, Hayden MR (2014) The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington’s disease. Hum Mol Genet 23:4142–4160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castaneda-Corral G, Rocha-Gonzalez HI, Godinez-Chaparro B, Jimenez-Andrade JM, Granados-Soto V (2011) Role of the spinal Na+/H+ exchanger in formalin-induced nociception. Neurosci Lett 501:4–9

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Wen J, Zheng Y, Yang H, Luo K, Liu Q, Hu R, Tan Z, Huang Q, Fu J (2015) Prognostic significance of SLC9A9 in patients with resectable esophageal squamous cell carcinoma. Tumour Biol 36:6797–6803

    Article  CAS  PubMed  Google Scholar 

  • Chinnapen DJ, Chinnapen H, Saslowsky D, Lencer WI (2007) Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER. FEMS Microbiol Lett 266:129–137

    Article  CAS  PubMed  Google Scholar 

  • Corominas R, Yang X, Lin GN, Kang S, Shen Y, Ghamsari L, Broly M, Rodriguez M, Tam S, Trigg SA, Fan C, Yi S, Tasan M, Lemmens I, Kuang X, Zhao N, Malhotra D, Michaelson JJ, Vacic V, Calderwood MA, Roth FP, Tavernier J, Horvath S, Salehi-Ashtiani K, Korkin D, Sebat J, Hill DE, Hao T, Vidal M, Iakoucheva LM (2014) Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun 5:3650

    Article  CAS  PubMed  Google Scholar 

  • Cremona ML, Matthies HJ, Pau K, Bowton E, Speed N, Lute BJ, Anderson M, Sen N, Robertson SD, Vaughan RA, Rothman JE, Galli A, Javitch JA, Yamamoto A (2011) Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat Neurosci 14:469–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daakour S, Hajingabo LJ, Kerselidou D, Devresse A, Kettmann R, Simonis N, Dequiedt F, Twizere JC (2016) Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor. BMC Cancer 16:335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daniels GM, Amara SG (1999) Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J Biol Chem 274:35794–35801

    Article  CAS  PubMed  Google Scholar 

  • de Silva MG, Elliott K, Dahl HH, Fitzpatrick E, Wilcox S, Delatycki M, Williamson R, Efron D, Lynch M, Forrest S (2003) Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype. J Med Genet 40:733–740

    Article  PubMed  PubMed Central  Google Scholar 

  • De Vito P (2006) The sodium/hydrogen exchanger: a possible mediator of immunity. Cell Immunol 240:69–85

    Article  CAS  PubMed  Google Scholar 

  • Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Belliveau R, Bybjerg-Grauholm J, Bækved-Hansen M, Cerrato F, Chambert K, Churchhouse C, Dumont A, Eriksson N, Gandal M, Goldstein J, Grove J, Hansen CS, Hauberg M, Hollegaard M, Howrigan DP, Huang H, Maller J, Martin AR, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Robinson EB, Satterstrom FK, Stevens C, Turley P, Won H, Andreassen OA, Burton C, Boomsma D, Cormand B, Dalsgaard S, Franke B, Gelernter J, Geschwind D, Hakonarson H, Haavik J, Kranzler H, Kuntsi J, Langley K, Lesch K-P, Middeldorp C, Reif A, Rohde LA, Roussos P, Schachar R, Sklar P, Sonuga-Barke E, Sullivan PF, Thapar A, Tung J, Waldman I, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Daly MJ, Faraone SV, Børglum AD, Neale BM (2017) Discovery of the first genome-wide significant risk loci for ADHD (submitted for publication)

  • Dobrowolski R, De Robertis EM (2011) Endocytic control of growth factor signalling: multivesicular bodies as signalling organelles. Nat Rev Mol Cell Biol 13:53–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esposito F, Sorosina M, Ottoboni L, Lim ET, Replogle JM, Raj T, Brambilla P, Liberatore G, Guaschino C, Romeo M, Pertel T, Stankiewicz JM, Martinelli V, Rodegher M, Weiner HL, Brassat D, Benoist C, Patsopoulos NA, Comi G, Elyaman W, Martinelli Boneschi F, De Jager PL (2015) A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol 78:115–127

    Article  CAS  PubMed  Google Scholar 

  • Esposito MR, Binatti A, Pantile M, Coppe A, Mazzocco K, Longo L, Capasso M, Lasorsa VA, Luksch R, Bortoluzzi S, Tonini GP (2018) Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients’ survival and indicate proteins targetable at onset of disease. Int J Cancer 143:2525–2536

    Article  CAS  PubMed  Google Scholar 

  • Faraone SV, Mick E (2010) Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin North Am 33:159–180

    Article  PubMed  PubMed Central  Google Scholar 

  • Faraone SV, Zhang-James Y (2013) Can sodium/hydrogen exchange inhibitors be repositioned for treating attention deficit hyperactivity disorder? An in silico approach. Am J Med Genet B Neuropsychiatr Genet 162B:711–717

    Article  PubMed  Google Scholar 

  • Friedman JR, Dibenedetto JR, West M, Rowland AA, Voeltz GK (2013) Endoplasmic reticulum-endosome contact increases as endosomes traffic and mature. Mol Biol Cell 24:1030–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guldbrandsen A, Vethe H, Farag Y, Oveland E, Garberg H, Berle M, Myhr KM, Opsahl JA, Barsnes H, Berven FS (2014) In-depth characterization of the cerebrospinal fluid (CSF) proteome displayed through the CSF proteome resource (CSF-PR). Mol Cell Proteomics 13:3152–3163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henningsson S, Jonsson L, Ljunggren E, Westberg L, Gillberg C, Rastam M, Anckarsater H, Nygren G, Landen M, Thuresson K, Betancur C, Leboyer M, Gillberg C, Eriksson E, Melke J (2009) Possible association between the androgen receptor gene and autism spectrum disorder. Psychoneuroendocrinology 34:752–761

    Article  CAS  PubMed  Google Scholar 

  • Hirling H (2009) Endosomal trafficking of AMPA-type glutamate receptors. Neuroscience 158:36–44

    Article  CAS  PubMed  Google Scholar 

  • Hisamitsu T, Ben Ammar Y, Nakamura TY, Wakabayashi S (2006) Dimerization is crucial for the function of the Na+/H+ exchanger NHE1. Biochemistry 45:13346–13355

    Article  CAS  PubMed  Google Scholar 

  • Hooper AJ, Burnett JR (2013) Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opin Biol Ther 13:429–435

    Article  CAS  PubMed  Google Scholar 

  • Hultman CM, Torrang A, Tuvblad C, Cnattingius S, Larsson JO, Lichtenstein P (2007) Birth weight and attention-deficit/hyperactivity symptoms in childhood and early adolescence: a prospective swedish twin study. J Am Acad Child Adolesc Psychiatry 46:370–377

    Article  PubMed  Google Scholar 

  • Jacunski M (2015) The role of NHE9 in vesicular trafficking and pH regulation. McGill University, Montreal

    Google Scholar 

  • Joseph N, Zhang-James Y, Perl A, Faraone SV (2015) Oxidative stress and ADHD: a meta-analysis. J Atten Disord 19:915–924

    Article  PubMed  Google Scholar 

  • Karaer K, Lissewski C, Zenker M (2015) Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation. Am J Med Genet A 167A:385–388

    Article  CAS  PubMed  Google Scholar 

  • Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R (2013) Functional evaluation of autism-associated mutations in NHE9. Nat Commun 4:2510

    Article  CAS  PubMed  Google Scholar 

  • Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–1714

    Article  CAS  PubMed  Google Scholar 

  • Lanz TA, Guilmette E, Gosink MM, Fischer JE, Fitzgerald LW, Stephenson DT, Pletcher MT (2013) Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action. Mol Autism 4:45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lasky-Su J, Anney RJ, Neale BM, Franke B, Zhou K, Maller JB, Vasquez AA, Chen W, Asherson P, Buitelaar J, Banaschewski T, Ebstein R, Gill M, Miranda A, Mulas F, Oades RD, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen HC, Taylor E, Daly M, Laird N, Lange C, Faraone SV (2008a) Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B:1355–1358

    Article  PubMed  PubMed Central  Google Scholar 

  • Lasky-Su J, Neale BM, Franke B, Anney RJ, Zhou K, Maller JB, Vasquez AA, Chen W, Asherson P, Buitelaar J, Banaschewski T, Ebstein R, Gill M, Miranda A, Mulas F, Oades RD, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen HC, Taylor E, Daly M, Laird N, Lange C, Faraone SV (2008b) Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet 147B:1345–1354

    Article  CAS  PubMed  Google Scholar 

  • Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayes M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisen L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kahler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landen M, Langstrom N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Muhleisen TW, Muir WJ, Muller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nothen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O’Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnstrom K, Reif A, Ribases M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zollner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O’Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994

    Article  CAS  PubMed  Google Scholar 

  • Lehoux S, Abe J, Florian JA, Berk BC (2001) 14-3-3 Binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange. J Biol Chem 276:15794–15800

    Article  CAS  PubMed  Google Scholar 

  • Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M, Hadjikhani N, Ben-Ari Y (2012) A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2:e202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu G, Zhang F, Hu Y, Jiang Y, Gong Z, Liu S, Chen X, Jiang Q, Hao J (2017) Genetic variants and multiple sclerosis risk gene SLC9A9 expression in distinct human brain regions. Mol Neurobiol 54:6820–6826

    Article  CAS  PubMed  Google Scholar 

  • Mahad D, Lassmann H, Turnbull D (2008) Review: mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol 34:577–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahoney DW, Therneau TM, Heppelmann CJ, Higgins L, Benson LM, Zenka RM, Jagtap P, Nelsestuen GL, Bergen HR, Oberg AL (2011) Relative quantification: characterization of bias, variability and fold changes in mass spectrometry data from iTRAQ-labeled peptides. J Proteome Res 10:4325–4333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malo ME, Fliegel L (2006) Physiological role and regulation of the Na+/H+ exchanger. Can J Physiol Pharmacol 84:1081–1095

    Article  CAS  PubMed  Google Scholar 

  • Markunas CA, Quinn KS, Collins AL, Garrett ME, Lachiewicz AM, Sommer JL, Morrissey-Kane E, Kollins SH, Anastopoulos AD, Ashley-Koch AE (2010) Genetic variants in SLC9A9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families. Psychiatr Genet 20:73–81

    Article  PubMed  PubMed Central  Google Scholar 

  • Martin-Negrier ML, Charron G, Bloch B (2006) Receptor recycling mediates plasma membrane recovery of dopamine D1 receptors in dendrites and axons after agonist-induced endocytosis in primary cultures of striatal neurons. Synapse 60:194–204

    Article  CAS  PubMed  Google Scholar 

  • Martinussen R, Tannock R (2006) Working memory impairments in children with attention-deficit hyperactivity disorder with and without comorbid language learning disorders. J Clin Exp Neuropsychol 28:1073–1094

    Article  PubMed  Google Scholar 

  • Mayle KM, Le AM, Kamei DT (2012) The intracellular trafficking pathway of transferrin. Biochim Biophys Acta 1820:264–281

    Article  CAS  PubMed  Google Scholar 

  • Melikian HE, Buckley KM (1999) Membrane trafficking regulates the activity of the human dopamine transporter. J Neurosci 19:7699–7710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monuteaux MC, Spencer TJ, Faraone SV, Wilson AM, Biederman J (2007) A randomized, placebo-controlled clinical trial of bupropion for the prevention of smoking in children and adolescents with attention-deficit/hyperactivity disorder. J Clin Psychiatry 68:1094–1101

    Article  CAS  PubMed  Google Scholar 

  • Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naegele Susanne, Morley Simon J (2004) Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress. J Biol Chem 279:46023–46034

    Article  CAS  PubMed  Google Scholar 

  • Nakamura N, Tanaka S, Teko Y, Mitsui K, Kanazawa H (2005) Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem 280:1561–1572

    Article  CAS  PubMed  Google Scholar 

  • Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng D, Hu N, Hu Y, Wang C, Giffen C, Tang ZZ, Han XY, Yang HH, Lee MP, Goldstein AM, Taylor PR (2008) Replication of a genome-wide case-control study of esophageal squamous cell carcinoma. Int J Cancer 123:1610–1615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ngounou Wetie AG, Wormwood K, Thome J, Dudley E, Taurines R, Gerlach M, Woods AG, Darie CC (2014) A pilot proteomic study of protein markers in autism spectrum disorder. Electrophoresis 35:2046–2054

    Article  CAS  PubMed  Google Scholar 

  • Ngounou Wetie AG, Wormwood KL, Charette L, Ryan JP, Woods AG, Darie CC (2015) Comparative two-dimensional polyacrylamide gel electrophoresis of the salivary proteome of children with autism spectrum disorder. J Cell Mol Med 19:2664–2678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nowaczyk MJ, Thompson BA, Zeesman S, Moog U, Sanchez-Lara PA, Magoulas PL, Falk RE, Hoover-Fong JE, Batista DA, Amudhavalli SM, White SM, Graham GE, Rauen KA (2014) Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet 85:138–146

    Article  CAS  PubMed  Google Scholar 

  • Oberg AL, Mahoney DW (2012) Statistical methods for quantitative mass spectrometry proteomic experiments with labeling. BMC Bioinform 13(Suppl 16):S7

    Article  CAS  Google Scholar 

  • Oberg AL, Vitek O (2009) Statistical design of quantitative mass spectrometry-based proteomic experiments. J Proteome Res 8:2144–2156

    Article  CAS  PubMed  Google Scholar 

  • Ohgaki R, Fukura N, Matsushita M, Mitsui K, Kanazawa H (2008) Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1. J Biol Chem 283:4417–4429

    Article  CAS  PubMed  Google Scholar 

  • Onuora S (2012) Crystal arthritis: canakinumab relieves gout flares when treatment options are limited. Nat Rev Rheumatol 8:369

    Article  PubMed  Google Scholar 

  • O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43:585–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O’Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–1622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palfy M, Remenyi A, Korcsmaros T (2012) Endosomal crosstalk: meeting points for signaling pathways. Trends Cell Biol 22:447–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park M, Penick EC, Edwards JG, Kauer JA, Ehlers MD (2004) Recycling endosomes supply AMPA receptors for LTP. Science 305:1972–1975

    Article  CAS  PubMed  Google Scholar 

  • Park M, Salgado JM, Ostroff L, Helton TD, Robinson CG, Harris KM, Ehlers MD (2006) Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52:817–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patak J, Zhang-James Y, Faraone SV (2016) Endosomal system genetics and autism spectrum disorders: a literature review. Neurosci Biobehav Rev 65:95–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patak J, Hess JL, Zhang-James Y, Glatt SJ, Faraone SV (2017) SLC9A9 Co-expression modules in autism-associated brain regions. Autism Res 10:414–429

    Article  PubMed  Google Scholar 

  • Pivac N, Knezevic A, Gornik O, Pucic M, Igl W, Peeters H, Crepel A, Steyaert J, Novokmet M, Redzic I, Nikolac M, Hercigonja VN, Curkovic KD, Curkovic M, Nedic G, Muck-Seler D, Borovecki F, Rudan I, Lauc G (2011) Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders. Mol Cell Proteomics 10(M110):004200

    PubMed  Google Scholar 

  • Poelmans G, Pauls DL, Buitelaar JK, Franke B (2011) Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatry 168:365–377

    Article  PubMed  Google Scholar 

  • Prasad V, Lorenz JN, Miller ML, Vairamani K, Nieman ML, Wang Y, Shull GE (2013) Loss of NHE1 activity leads to reduced oxidative stress in heart and mitigates high-fat diet-induced myocardial stress. J Mol Cell Cardiol 65:33–42

    Article  CAS  PubMed  Google Scholar 

  • Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506

    Article  CAS  PubMed  Google Scholar 

  • Raught B, Gingras AC (1999) eIF4E activity is regulated at multiple levels. Int J Biochem Cell Biol 31:43–57

    Article  CAS  PubMed  Google Scholar 

  • Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocha MA, Crockett DP, Wong LY, Richardson JR, Sonsalla PK (2008) Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions. J Neurochem 106:231–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sager JJ, Torres GE (2011) Proteins interacting with monoamine transporters: current state and future challenges. Biochemistry 50:7295–7310

    Article  CAS  PubMed  Google Scholar 

  • Sagvolden T, Dasbanerjee T, Zhang-James Y, Middleton F, Faraone S (2008) Behavioral and genetic evidence for a novel animal model of Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype. Behav Brain Funct 4:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, Zoghbi HY (2011) Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med 3:86ra49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schelling JR, Abu Jawdeh BG (2008) Regulation of cell survival by Na+/H+ exchanger-1. Am J Physiol Renal Physiol 295:F625–F632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlesinger N (2012) Canakinumab in gout. Expert Opin Biol Ther 12:1265–1275

    Article  CAS  PubMed  Google Scholar 

  • Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smaga I, Niedzielska E, Gawlik M, Moniczewski A, Krzek J, Przegalinski E, Pera J, Filip M (2015) Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. Pharmacol Rep 67:569–580

    Article  CAS  PubMed  Google Scholar 

  • Smyth GK, Speed T (2003) Normalization of cDNA microarray data. Methods 31:265–273

    Article  CAS  PubMed  Google Scholar 

  • Solomon M, Frank MJ, Ragland JD, Smith AC, Niendam TA, Lesh TA, Grayson DS, Beck JS, Matter JC, Carter CS (2015) Feedback-driven trial-by-trial learning in autism spectrum disorders. Am J Psychiatry 172:173–181

    Article  PubMed  Google Scholar 

  • Sowerby P, Seal S, Tripp G (2011) Working memory deficits in ADHD: the contribution of age, learning/language difficulties, and task parameters. J Atten Disord 15:461–472

    Article  PubMed  Google Scholar 

  • Taurines R, Dudley E, Conner AC, Grassl J, Jans T, Guderian F, Mehler-Wex C, Warnke A, Gerlach M, Thome J (2010) Serum protein profiling and proteomics in autistic spectrum disorder using magnetic bead-assisted mass spectrometry. Eur Arch Psychiatry Clin Neurosci 260:249–255

    Article  PubMed  Google Scholar 

  • Turkewitz AP, Amatruda JF, Borhani D, Harrison SC, Schwartz AL (1988) A high yield purification of the human transferrin receptor and properties of its major extracellular fragment. J Biol Chem 263:8318–8325

    CAS  PubMed  Google Scholar 

  • Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE (2007) Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet 8:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ullman JC, Yang J, Sullivan M, Bendor J, Levy J, Pham E, Silm K, Seifikar H, Sohal VS, Nicoll RA, Edwards RH (2018) A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry. Nat Commun 9:330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urban D, Poss J, Bohm M, Laufs U (2013) Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62:1401–1408

    Article  CAS  PubMed  Google Scholar 

  • Verma D, Eriksson P, Sahdo B, Persson A, Ejdeback M, Sarndahl E, Soderkvist P (2010) Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP3. Arthritis Rheum 62:2138–2143

    CAS  PubMed  Google Scholar 

  • Wagle M, Holder J (2014) Exonic deletion of SLC9A9 in autism with epilepsy. Neurology 82:P4.338

    Google Scholar 

  • Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, Thapar A, O’Donovan MC, Owen MJ, Holmans P, Kent L, Middleton F, Zhang-James Y, Liu L, Meyer J, Nguyen TT, Romanos J, Romanos M, Seitz C, Renner TJ, Walitza S, Warnke A, Palmason H, Buitelaar J, Rommelse N, Vasquez AA, Hawi Z, Langley K, Sergeant J, Steinhausen HC, Roeyers H, Biederman J, Zaharieva I, Hakonarson H, Elia J, Lionel AC, Crosbie J, Marshall CR, Schachar R, Scherer SW, Todorov A, Smalley SL, Loo S, Nelson S, Shtir C, Asherson P, Reif A, Lesch KP, Faraone SV (2012) Genome-wide analysis of copy number variants in attention deficit/hyperactivity disorder confirms the role of rare variants and implicates duplications at 15q13.3. Am J Psychiatry 169:195–204

    Article  PubMed  PubMed Central  Google Scholar 

  • Woods AG, Ngounou Wetie AG, Sokolowska I, Russell S, Ryan JP, Michel TM, Thome J, Darie CC (2013) Mass spectrometry as a tool for studying autism spectrum disorder. J Mol Psychiatry 1:6

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang L, Neale BM, Liu L, Lee SH, Wray NR, Ji N, Li H, Qian Q, Wang D, Li J, Faraone SV, Wang Y (2013) Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am J Med Genet B Neuropsychiatr Genet 162:419–430

    Article  CAS  Google Scholar 

  • Yang L, Faraone SV, Zhang-James Y (2016) Autism spectrum disorder traits in Slc9a9 knock-out mice. Am J Med Genet B Neuropsychiatr Genet 171B:363–376

    Article  CAS  PubMed  Google Scholar 

  • Zafeiriou DI, Ververi A, Dafoulis V, Kalyva E, Vargiami E (2013) Autism spectrum disorders: the quest for genetic syndromes. Am J Med Genet B Neuropsychiatr Genet 162B:327–366

    Article  CAS  PubMed  Google Scholar 

  • Zayats T, Athanasiu L, Sonderby I, Djurovic S, Westlye LT, Tamnes CK, Fladby T, Aase H, Zeiner P, Reichborn-Kjennerud T, Knappskog PM, Knudsen GP, Andreassen OA, Johansson S, Haavik J (2015) Genome-wide analysis of attention deficit hyperactivity disorder in Norway. PLoS ONE 10:e0122501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang-James Y, DasBanerjee T, Sagvolden T, Middleton FA, Faraone SV (2011) SLC9A9 mutations, gene expression, and protein-protein interactions in rat models of attention-deficit/hyperactivity disorder. Am J Med Genet Part B Neuropsychiatr Genet 156:835–843

    Article  CAS  Google Scholar 

  • Zhang-James Y, Middleton FA, Sagvolden T, Faraone SV (2012) Differential expression of SLC9A9 and interacting molecules in the hippocampus of rat models for attention deficit/hyperactivity disorder. Dev Neurosci 34:218–227

    Article  CAS  PubMed  Google Scholar 

  • Zhang-James Y, Yang L, Middleton FA, Yang L, Patak J, Faraone SV (2014) Autism-related behavioral phenotypes in an inbred rat substrain. Behav Brain Res 269:103–114

    Article  PubMed  Google Scholar 

  • Zheng CF, Guan KL (1993a) Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem 268:11435–11439

    CAS  PubMed  Google Scholar 

  • Zheng CF, Guan KL (1993b) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268:23933–23939

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Hanno Steen for helpful advice on proteomics and comments on the manuscript. This work was supported by Stiftelsen Kristian Gerhard Jebsen (SKGJ-MED-002 to Haavik), NIH Grant 5R01MH066877 (Stephen V Faraone, PI) and a NARSAD Young Investigator Award to Yanli Zhang-James. Dr. Faraone is supported by the K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant Agreement No 602805, the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 667302 and NIMH Grant 5R01MH101519.

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Authors and Affiliations

  1. Departments of Psychiatry, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY, 13210, USA

    Yanli Zhang-James & Stephen V. Faraone

  2. Department of Clinical Science, University of Bergen, Bergen, Norway

    Marc Vaudel

  3. Department of Biomedicine, University of Bergen, Bergen, Norway

    Olav Mjaavatten, Frode S. Berven & Jan Haavik

  4. K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway

    Jan Haavik

  5. Division of Psychiatry, Haukeland University Hospital, Bergen, Norway

    Jan Haavik

  6. Neuroscience and Physiology, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY, 13210, USA

    Stephen V. Faraone

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  1. Yanli Zhang-James
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Correspondence to Stephen V. Faraone.

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Conflict of interest

Yanli Zhang-James, Frode S. Berven, Olav Mjaavatten, Marc Vaudel and Hanno Steen declare no conflict of interest. During the past three years, Jan Haavik has received speaker fees from Lilly, Novartis, Shire, Medice, HB Pharma and Janssen-Cilag. In the past year, Dr. Faraone received income, travel expenses and/or research support from and/or has been on an Advisory Board for Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, NeuroLifeSciences and research support from the National Institutes of Health (NIH). With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier, ADHD: Non-Pharmacologic Treatments.

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This manuscript is in response to a special issue honoring Prof. Jan Buitelaar.

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Supplementary Figure 1

A TMT experimental design showing Co-IP samples and TMT labeling. A total of four MS samples were conducted in our study by combining equal amount of Co-IP samples that were labeled with randomly assigned TMT labels. For MS sample labeled as “WT,” a total of 6 samples were combined including three replicates of WT co-IP samples and their corresponding negative control samples (CT). The corresponding TMT ratios that were used in analysis and shown in Figure B were labeled following the order of “MS sample name,” “numerator sample name” and “denominator sample names.” Therefore, three ratios were obtained from the 6-plex MS sample “WT”: “wt_wt1ct1,” “wt_wt2ct2” and “wt_wt3ct3.” Three other MS samples (named mut1, mut2, mut3) each was generated by combining a set of three parallel-processed Co-IP samples, the WT, AP and their corresponding CT samples. The ratios of WT versus CT and AP versus CT were obtained from each set. Therefore, a total of 6 TMT ratios were obtained from these three MS samples, and they were labeled in Figure B following the same naming convention. BTMT raw ratios (Left) were log-transformed (Middle) and normalized (Right). (PDF 244 kb)

Supplementary Figure 2

Distribution of percentage of protein coverage, the numbers of PSMs and peptides identified for each protein were plotted against the normalized mean WT versus CT ratios (Top row) and the Z test negative log p values (Bottom row) to show that these factors do not influence the Z test-based PPI filtering. (PDF 117 kb)

Supplementary Figure 3

Known interactions form a single connected network for WT (A) and AP (B) proteins. The degree of each node is proportional to size. Significantly changed proteins (Z test p < 0.05) by A409P mutation are colored, with green indicating decreased interactions and red indicating increased interactions. The color intensity is proportional to the averaged AP versus WT ratios (log2 ratios), i.e., the log2 fold change of binding to NHE9 due to the mutation. Proteins that did not show significant changes are white. Notice the loss of MAP2K2 and a big hub node, VIM in the AP network, as well as a number of increased interactions such as FLOT1. (PDF 1177 kb)

Supplementary Figure 4

Transferrin (TF) and cholera toxin beta subunit (CTB) endocytosis in N2a cells. A Representative images of TF and CTB staining (green) at 30 min are shown. TF uniformly labels almost all cells; however, CTB labeling in N2a cells is more heterogeneous. DAPI nuclei stain is blue. B, C show representative 10 × images of TF (B) and CTB (C) labeling for different groups at different time points. (PDF 2127 kb)

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Supplementary file 3 (XLS 43 kb)

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Zhang-James, Y., Vaudel, M., Mjaavatten, O. et al. Effect of disease-associated SLC9A9 mutations on protein–protein interaction networks: implications for molecular mechanisms for ADHD and autism. ADHD Atten Def Hyp Disord 11, 91–105 (2019). https://doi.org/10.1007/s12402-018-0281-x

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