Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia


Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium–potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. 1.

    Driver DI, Gogtay N, Rapoport JL. Childhood onset schizophrenia and early onset schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2013;22:539–55.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Giannitelli M, Consoli A, Raffin M, Jardri R, Levinson DF, Cohen D, et al. An overview of medical risk factors for childhood psychosis: implications for research and treatment. Schizophr Res. 2017. https://doi.org/10.1016/j.schres.2017.05.011.

  3. 3.

    McKenna K, Gordon CT, Lenane M, Kaysen D, Fahey K, Rapoport JL. Looking for childhood-onset schizophrenia: the first 71 cases screened. J Am Acad Child Adolesc Psychiatry. 1994;33:636–44.

    CAS  PubMed  Google Scholar 

  4. 4.

    Asarnow RF, Forsyth JK. Genetics of childhood-onset schizophrenia. Child Adolesc Psychiatr Clin N Am. 2013;22:675–87.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ahn K, Gotay N, Andersen TM, Anvari AA, Gochman P, Lee Y, et al. High rate of disease-related copy number variations in childhood onset schizophrenia. Mol Psychiatry. 2014;19:568–72.

    CAS  PubMed  Google Scholar 

  6. 6.

    Zhou D, Gochman P, Broadnax DD, Rapoport JL, Ahn K. 15q13.3 duplication in two patients with childhood-onset schizophrenia. Am J Med Genet Part B Neuropsychiatr Genet Publ Int Soc Psychiatr Genet. 2016;171:777–83.

    CAS  Google Scholar 

  7. 7.

    Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9.

    CAS  PubMed  Google Scholar 

  8. 8.

    Ambalavanan A, Girard SL, Ahn K, Zhou S, Dionne-Laporte A, Spiegelman D, et al. De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet (EJHG). 2015. https://doi.org/10.1038/ejhg.2015.218.

  9. 9.

    Tenney JR, Schapiro MB. Child neurology: alternating hemiplegia of childhood. Neurology. 2010;74:e57–59.

    PubMed  Google Scholar 

  10. 10.

    Brashear A, Sweadner KJ, Cook JF, Swoboda KJ, Ozelius L. ATP1A3-Related neurologic disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al.. (eds). GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1115/.

    Google Scholar 

  11. 11.

    Smedemark-Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, et al. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Cold Spring Harb Mol Case Stud. 2016;2. https://doi.org/10.1101/mcs.a001008.

  12. 12.

    Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, et al. Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep. 2018;22:734–47.

    CAS  PubMed  Google Scholar 

  13. 13.

    Gochman P, Miller R, Rapoport JL. Childhood-onset schizophrenia: the challenge of diagnosis. Curr Psychiatry Rep. 2011;13:321–2.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-wheeler transform. Bioinformatics. 2009;25:1754–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinforma Oxf Engl. 2009;25:2078–9.

    Google Scholar 

  16. 16.

    Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinforma. 2013;43:11.10.1–33.

    Google Scholar 

  17. 17.

    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164–e164.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRINGv10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–452.

    CAS  PubMed  Google Scholar 

  19. 19.

    Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2016;44:D481–487.

    CAS  PubMed  Google Scholar 

  20. 20.

    Melé M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. Human genomics. Human Transcr Across Tissues Individ Sci. 2015;348:660–5.

    Google Scholar 

  21. 21.

    Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature. 2011;478:519–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12.

    CAS  PubMed  Google Scholar 

  23. 23.

    Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012;44:1030–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Andreasen NC. Methods for assessing positive and negative symptoms1. Mod Probl Pharm. 1990;24:73–88.

    CAS  Google Scholar 

  26. 26.

    Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46:944–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    May P, Dencker S, Hubbard J. A systematic approach to treatment resistance in schizophrenic disorders. In: Dencker SJ, Kulhanek F, editors. Treatment Resistance in Schizophrenia. Braunschweig/Wiesbaden: Viewag Verlag; 1988. p. 22–3.

    Google Scholar 

  29. 29.

    Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom MCP. 2014;13:397–406.

    CAS  Google Scholar 

  30. 30.

    Lingrel JB, Kuntzweiler T. Na+,K(+)-ATPase. J Biol Chem. 1994;269:19659–62.

    CAS  PubMed  Google Scholar 

  31. 31.

    Geering K. FXYD proteins: new regulators of Na-K-ATPase. Am J Physiol – Ren Physiol. 2006;290:F241–F250.

    CAS  Google Scholar 

  32. 32.

    Garty H, Karlish SJD. Role of FXYD proteins in ion transport. Annu Rev Physiol. 2006;68:431–59.

    CAS  PubMed  Google Scholar 

  33. 33.

    Geering K, Béguin P, Garty H, Karlish S, Füzesi M, Horisberger J-D, et al. FXYD proteins: new tissue- and isoform-specific regulators of Na,K-ATPase. Ann N Y Acad Sci. 2003;986:388–94.

    CAS  PubMed  Google Scholar 

  34. 34.

    Li Z, Langhans SA Transcriptional regulators of Na,K-ATPase subunits. Front Cell Dev Biol. 2015;3. https://doi.org/10.3389/fcell.2015.00066.

  35. 35.

    Deng V, Matagne V, Banine F, Frerking M, Ohliger P, Budden S, et al. FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet. 2007;16:640–50.

    CAS  PubMed  Google Scholar 

  36. 36.

    Mounsey JP, Lu KP, Patel MK, Chen ZH, Horne LT, John JE, et al. Modulation of Xenopus oocyte-expressed phospholemman-induced ion currents by co-expression of protein kinases. Biochim Biophys Acta. 1999;1451:305–18.

    CAS  PubMed  Google Scholar 

  37. 37.

    Crambert G, Fuzesi M, Garty H, Karlish S, Geering K. Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties. Proc Natl Acad Sci USA. 2002;99:11476–81.

    CAS  PubMed  Google Scholar 

  38. 38.

    Kadowaki K, Sugimoto K, Yamaguchi F, Song T, Watanabe Y, Singh K, et al. Phosphohippolin expression in the rat central nervous system. Mol Brain Res. 2004;125:105–12.

    CAS  PubMed  Google Scholar 

  39. 39.

    Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol. 2015;52:56–64.

    PubMed  Google Scholar 

  40. 40.

    Panagiotakaki E, De Grandis E, Stagnaro M, Heinzen EL, Fons C, Sisodiya S, et al. Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood – a study of 155 patients. Orphanet J Rare Dis. 2015;10:123.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sweney MT, Silver K, Gerard-Blanluet M, Pedespan J-M, Renault F, Arzimanoglou A, et al. Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics. 2009;123:e534–e541.

    PubMed  Google Scholar 

  43. 43.

    Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K, Takada S, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology. 2014;82:482–90.

    CAS  PubMed  Google Scholar 

  44. 44.

    Muriel V, Garcia-Molina A, Aparicio-Lopez C, Ensenat A, Roig-Rovira T. Neuropsychological deficits in alternating hemiplegia of childhood: a case study. Rev Neurol. 2015;61:25–28.

    PubMed  Google Scholar 

  45. 45.

    Hoei-Hansen CE, Dali Cí, Lyngbye TJB, Duno M, Uldall P. Alternating hemiplegia of childhood in Denmark: clinical manifestations and ATP1A3 mutation status. Eur J Paediatr Neurol. 2014;18:50–54.

    PubMed  Google Scholar 

  46. 46.

    Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009;48:10–18.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Barbano RL, Hill DF, Snively BM, Light LS, Boggs N, McCall WV, et al. New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. Park Relat Disord. 2012;18:737–41.

    Google Scholar 

  48. 48.

    Brashear A, Cook JF, Hill DF, Amponsah A, Snively BM, Light L, et al. Psychiatric disorders in rapid-onset dystonia-parkinsonism. Neurology. 2012;79:1168–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Cook JF, Hill DF, Snively BM, Boggs N, Suerken CK, Haq I, et al. Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord J Mov Disord Soc. 2014;29:344–50.

    CAS  Google Scholar 

  50. 50.

    MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis DA, et al. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol Psychiatry. 2015;77:959–68.

    CAS  PubMed  Google Scholar 

  51. 51.

    Holm TH, Isaksen TJ, Glerup S, Heuck A, Bøttger P, Füchtbauer E-M, et al. Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform. Sci Rep. 2016;6. https://doi.org/10.1038/srep31972.

  52. 52.

    Biesemann C, Grønborg M, Luquet E, Wichert SP, Bernard V, Bungers SR, et al. Proteomic screening of glutamatergic mouse brain synaptosomes isolated by fluorescence activated sorting. EMBO J. 2014;33:157–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Stansberg C, Ersland KM, van der Valk P, Steen VM. Gene expression in the rat brain: high similarity but unique differences between frontomedial-, temporal- and occipital cortex. BMC Neurosci. 2011;12:15.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Ito Y, Nakamura Y, Takahashi N, Saito S, Aleksic B, Iwata N, et al. A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population. Neurosci Lett. 2008;438:70–75.

    CAS  PubMed  Google Scholar 

  55. 55.

    Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, et al. A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am J Hum Genet. 2007;80:664–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Zhong N, Zhang R, Qiu C, Yan H, Valenzuela RK, Zhang H, et al. A novel replicated association between FXYD6 gene and schizophrenia. Biochem Biophys Res Commun. 2011;405:118–21.

    CAS  PubMed  Google Scholar 

  57. 57.

    Jiao L, Wang B, Niu X, Ma X, Li J, Shen B, et al. A family-based association study of FXYD6 gene polymorphisms and schizophrenia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi Zhonghua Yixue Yichuanxue Zazhi Chin J Med Genet. 2011;28:539–42.

    CAS  Google Scholar 

  58. 58.

    Iwata Y, Yamada K, Iwayama Y, Anitha A, Thanseem I, Toyota T, et al. Failure to confirm genetic association of the FXYD6 gene with schizophrenia: the Japanese population and meta-analysis. Am J Med Genet Part B Neuropsychiatr Genet Publ Int Soc Psychiatr Genet. 2010;153B:1221–7.

    CAS  Google Scholar 

  59. 59.

    Hemby SE, Ginsberg SD, Brunk B, Arnold SE, Trojanowski JQ, Eberwine JH. Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex. Arch Gen Psychiatry. 2002;59:631–40.

    CAS  PubMed  Google Scholar 

  60. 60.

    Chang JT, Lowery LA, Sive H. Multiple roles for the Na,K-ATPase subunits, Atp1a1 and Fxyd1, during brain ventricle development. Dev Biol. 2012;368:312–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Banine F, Matagne V, Sherman LS, Ojeda SR. Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms. J Neurosci Res. 2011;89:840–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Cohen D, Lazar G, Couvert P, Desportes V, Lippe D, Mazet P, et al. MECP2 mutation in a boy with language disorder and schizophrenia. Am J Psychiatry. 2002;159:148–9.

    PubMed  Google Scholar 

  63. 63.

    Shiina N, Yamaguchi K, Tokunaga M. RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ATPase subunit isoforms and leads to the degeneration of neuronal networks. J Neurosci J Soc Neurosci. 2010;30:12816–30.

    CAS  Google Scholar 

  64. 64.

    Rosewich H, Sweney MT, DeBrosse S, Ess K, Ozelius L, Andermann E, et al. Research conference summary from the 2014 international task force on ATP1A3-related disorders. Neurol Genet. 2017;3:e139.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kumra S, Oberstar JV, Sikich L, Findling RL, McClellan JM, Vinogradov S, et al. Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia. Schizophr Bull. 2008;34:60–71.

    PubMed  Google Scholar 

  66. 66.

    Ju J, Hirose S, Shi X-Y, Ishii A, Hu L-Y, Zou L-P. Treatment with oral ATP decreases alternating hemiplegia of childhood with de novo ATP1A3 Mutation. Orphanet J Rare Dis. 2016;11:55.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Consoli A, Raffin M, Laurent C, Bodeau N, Campion D, Amoura Z, et al. Medical and developmental risk factors of catatonia in children and adolescents: a prospective case-control study. Schizophr Res. 2012;137:151–8.

    PubMed  Google Scholar 

  68. 68.

    Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis. 2014;9:65.

    PubMed  PubMed Central  Google Scholar 

Download references


We thank the patients and the family members who participate in the study as well as the involved medical teams. We thank Daniel Rochefort and Sylvia Dobrezenicka for the technical support; also Edouard Henrion and Ousmane Diallo for their bioinformatics support. We also thank Dr Maryam Soleimani and Dr Laure Bera for their comments, as well as Dr Elodie Hainque for her advice.


The American cohort was supported by the National institute of Mental health (NIMH). Its genetic assessment was supported by the Genome Canada and Genome Quebec (Grant No. RMF_92086). Bioinformatics analysis was supported by the Canadian Institutes of Health Research (CIHR). Boris Chaumette receives a postdoctoral fellowship from the Healthy Brains for Healthy Lives project (Talent program).

Author information



Corresponding author

Correspondence to Guy A. Rouleau.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chaumette, B., Ferrafiat, V., Ambalavanan, A. et al. Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia. Mol Psychiatry 25, 821–830 (2020). https://doi.org/10.1038/s41380-018-0103-8

Download citation

Further reading