Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity

Molecular Psychiatry volume 28, pages 1219–1231 (2023)Cite this article

Subjects

Abstract

ATP9A, a lipid flippase of the class II P4-ATPases, is involved in cellular vesicle trafficking. Its homozygous variants are linked to neurodevelopmental disorders in humans. However, its physiological function, the underlying mechanism as well as its pathophysiological relevance in humans and animals are still largely unknown. Here, we report two independent families in which the nonsense mutations c.433C>T/c.658C>T/c.983G>A (p. Arg145*/p. Arg220*/p. Trp328*) in ATP9A (NM_006045.3) cause autosomal recessive hypotonia, intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD). Atp9a null mice show decreased muscle strength, memory deficits and hyperkinetic movement disorder, recapitulating the symptoms observed in patients. Abnormal neurite morphology and impaired synaptic transmission are found in the primary motor cortex and hippocampus of the Atp9a null mice. ATP9A is also required for maintaining neuronal neurite morphology and the viability of neural cells in vitro. It mainly localizes to endosomes and plays a pivotal role in endosomal recycling pathway by modulating small GTPase RAB5 and RAB11 activation. However, ATP9A pathogenic mutants have aberrant subcellular localization and cause abnormal endosomal recycling. These findings provide strong evidence that ATP9A deficiency leads to neurodevelopmental disorders and synaptic dysfunctions in both humans and mice, and establishes novel regulatory roles for ATP9A in RAB5 and RAB11 activity-dependent endosomal recycling pathway and neurological diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pedigrees, genetic testing and identification of ATP9A mutations.
Fig. 2: Atp9a null mice show muscle weakness, memory impairment and hyperkinetic movement disorders.
Fig. 3: ATP9A is required for the maintenance of neuronal neurite morphology, synaptic transmission and cell survival.
Fig. 4: ATP9A mainly localizes to endosomes, and pathogenic mutants of ATP9A form intracellular aggregates and exhibit altered intracellular distribution.
Fig. 5: Depletion or mutation of ATP9A affects the distribution of RAB11 and delays TFN recycling.
Fig. 6: ATP9A promotes the activation of RAB5 and RAB11.

Similar content being viewed by others

Data availability

All data are available in the main text or the supplementary information at MP’s website.

References

  1. Mehregan H, Najmabadi H, Kahrizi K. Genetic studies in intellectual disability and behavioral impairment. Arch Iran Med. 2016;19:363–75.

    PubMed  Google Scholar 

  2. Stevenson RE, Procopio-Allen AM, Schroer RJ, Collins JS. Genetic syndromes among individuals with mental retardation. Am J Med Genet A. 2003;123A:29–32.

    PubMed  Google Scholar 

  3. Klein M, Onnink M, van Donkelaar M, Wolfers T, Harich B, Shi Y, et al. Brain imaging genetics in ADHD and beyond–mapping pathways from gene to disorder at different levels of complexity. Neurosci Biobehav Rev. 2017;80:115–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Association AP. Diagnostic and statistical manual of mental disorders: DSM-5. Washington, DC: American Psychiatric Association; 2013.

  5. van Bokhoven H. Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet. 2011;45:81–104.

    PubMed  Google Scholar 

  6. Franke B, Neale BM, Faraone SV. Genome-wide association studies in ADHD. Hum Genet. 2009;126:13–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Online Mendelian Inheritance in Man. OMIM. Maryland: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University; 2020.

  8. Vogt G, Verheyen S, Schwartzmann S, Ehmke N, Potratz C, Schwerin-Nagel A, et al. Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive. J Med Genet. 2022;59:662–8.

    CAS  PubMed  Google Scholar 

  9. Mattioli F, Darvish H, Paracha SA, Tafakhori A, Firouzabadi SG, Chapi M, et al. Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder. NPJ Genom Med. 2021;6:94.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fazia T, Marzanati D, Carotenuto AL, Beecham A, Hadjixenofontos A, McCauley JL, et al. Homozygosity haplotype and whole-exome sequencing analysis to identify potentially functional rare variants involved in multiple sclerosis among sardinian families. Curr Issues Mol Biol. 2021;43:1778–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hiraizumi M, Yamashita K, Nishizawa T, Nureki O. Cryo-EM structures capture the transport cycle of the P4-ATPase flippase. Science. 2019;365:1149–55.

    CAS  PubMed  Google Scholar 

  12. Andersen JP, Vestergaard AL, Mikkelsen SA, Mogensen LS, Chalat M, Molday RS. P4-ATPases as phospholipid flippases-structure, function, and enigmas. Front Physiol. 2016;7:275.

    PubMed  PubMed Central  Google Scholar 

  13. Sebastian TT, Baldridge RD, Xu P, Graham TR. Phospholipid flippases: building asymmetric membranes and transport vesicles. Biochim Biophys Acta. 2012;1821:1068–77.

    CAS  PubMed  Google Scholar 

  14. Levano K, Punia V, Raghunath M, Debata PR, Curcio GM, Mogha A, et al. Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning. J Neurochem. 2012;120:302–13.

    CAS  PubMed  Google Scholar 

  15. Guissart C, Harrison AN, Benkirane M, Oncel I, Arslan EA, Chassevent AK, et al. ATP8A2-related disorders as recessive cerebellar ataxia. J Neurol. 2019;267:203–13.

    PubMed  Google Scholar 

  16. Wang J, Li W, Zhou F, Feng R, Wang F, Zhang S, et al. ATP11B deficiency leads to impairment of hippocampal synaptic plasticity. J Mol Cell Biol. 2019;11:688–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009;136:1060–9.

    CAS  PubMed  Google Scholar 

  18. de Waart DR, Naik J, Utsunomiya KS, Duijst S, Ho-Mok K, Bolier AR, et al. ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes. Hepatology. 2016;64:161–74.

    PubMed  Google Scholar 

  19. Dhar MS, Sommardahl CS, Kirkland T, Nelson S, Donnell R, Johnson DK, et al. Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes. J Nutr. 2004;134:799–805.

    CAS  PubMed  Google Scholar 

  20. Siggs OM, Arnold CN, Huber C, Pirie E, Xia Y, Lin P, et al. The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow. Nat Immunol. 2011;12:434–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. van der Mark VA, Elferink RP, Paulusma CC. P4 ATPases: flippases in health and disease. Int J Mol Sci. 2013;14:7897–922.

    PubMed  PubMed Central  Google Scholar 

  22. Hua Z, Fatheddin P, Graham TR. An essential subfamily of Drs2p-related P-type ATPases is required for protein trafficking between Golgi complex and endosomal/vacuolar system. Mol Biol Cell. 2002;13:3162–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lyssenko NN, Miteva Y, Gilroy S, Hanna-Rose W, Schlegel RA. An unexpectedly high degree of specialization and a widespread involvement in sterol metabolism among the C. elegans putative aminophospholipid translocases. BMC Dev Biol. 2008;8:96.

    PubMed  PubMed Central  Google Scholar 

  24. Efe JA, Plattner F, Hulo N, Kressler D, Emr SD, Deloche O. Yeast Mon2p is a highly conserved protein that functions in the cytoplasm-to-vacuole transport pathway and is required for Golgi homeostasis. J Cell Sci. 2005;118:4751–64.

    CAS  PubMed  Google Scholar 

  25. Beer KB, Rivas-Castillo J, Kuhn K, Fazeli G, Karmann B, Nance JF, et al. Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry. Proc Natl Acad Sci USA. 2018;115:E1127–E1136.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Naik J, Hau CM, Ten Bloemendaal L, Mok KS, Hajji N, Wehman AM, et al. The P4-ATPase ATP9A is a novel determinant of exosome release. PLoS ONE. 2019;14:e0213069.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tanaka Y, Ono N, Shima T, Tanaka G, Katoh Y, Nakayama K, et al. The phospholipid flippase ATP9A is required for the recycling pathway from the endosomes to the plasma membrane. Mol Biol Cell. 2016;27:3883–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. McGough IJ, de Groot REA, Jellett AP, Betist MC, Varandas KC, Danson CM, et al. SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nat Commun. 2018;9:3737.

    PubMed  PubMed Central  Google Scholar 

  29. Li X, DiFiglia M. The recycling endosome and its role in neurological disorders. Prog Neurobiol. 2012;97:127–41.

    CAS  PubMed  Google Scholar 

  30. O’Sullivan MJ, Lindsay AJ. The endosomal recycling pathway-at the crossroads of the cell. Int J Mol Sci. 2020;21:6074.

    PubMed  PubMed Central  Google Scholar 

  31. Veleri S, Punnakkal P, Dunbar GL, Maiti P. Molecular insights into the roles of rab proteins in intracellular dynamics and neurodegenerative diseases. Neuromol Med. 2018;20:18–36.

    CAS  Google Scholar 

  32. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10:513–25.

    CAS  PubMed  Google Scholar 

  33. Mitra J, Hegde PM, Hegde ML. Loss of endosomal recycling factor RAB11 coupled with complex regulation of MAPK/ERK/AKT signaling in postmortem spinal cord specimens of sporadic amyotrophic lateral sclerosis patients. Mol Brain. 2019;12:55.

    PubMed  PubMed Central  Google Scholar 

  34. Mlinac ME, Feng MC. Assessment of activities of daily living, self-care, and independence. Arch Clin Neuropsychol. 2016;31:506–16.

    PubMed  Google Scholar 

  35. Yang J, Hu L, Zhang Y, Shi Y, Jiang W, Song C. Gesell Developmental Schedules scores and the relevant factors in children with Down syndrome. J Pediatr Endocrinol Metab. 2020;33:539–46.

    PubMed  Google Scholar 

  36. Group BMDC. Gesell developmental diagnosis scale. Beijing: Beijing Mental Development Cooperative Group; 1985.

  37. Võikar V, Rauvala H, Ikonen E. Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease. Behav Brain Res. 2002;132:1–10.

    PubMed  Google Scholar 

  38. Matsuo N, Tanda K, Nakanishi K, Yamasaki N, Toyama K, Takao K, et al. Comprehensive behavioral phenotyping of ryanodine receptor type 3 (RyR3) knockout mice: decreased social contact duration in two social interaction tests. Front Behav Neurosci. 2009;3:3.

    PubMed  PubMed Central  Google Scholar 

  39. Takatsu H, Baba K, Shima T, Umino H, Kato U, Umeda M, et al. ATP9B, a P4-ATPase (a putative aminophospholipid translocase), localizes to the trans-Golgi network in a CDC50 protein-independent manner. J Biol Chem. 2011;286:38159–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schröter CJ, Braun M, Englert J, Beck H, Schmid H, Kalbacher H. A rapid method to separate endosomes from lysosomal contents using differential centrifugation and hypotonic lysis of lysosomes. J Immunol Methods. 1999;227:161–8.

    PubMed  Google Scholar 

  41. Mayle KM, Le AM, Kamei DT. The intracellular trafficking pathway of transferrin. Biochim Biophys Acta. 2012;1820:264–81.

    CAS  PubMed  Google Scholar 

  42. Ren M, Xu G, Zeng J, De Lemos-Chiarandini C, Adesnik M, Sabatini DD. Hydrolysis of GTP on rab11 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci USA. 1998;95:6187–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Stenmark H, Parton RG, Steele-Mortimer O, Lutcke A, Gruenberg J, Zerial M. Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J. 1994;13:1287–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ullrich O, Reinsch S, Urbe S, Zerial M, Parton RG. Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol. 1996;135:913–24.

    CAS  PubMed  Google Scholar 

  45. Knodler A, Feng S, Zhang J, Zhang X, Das A, Peranen J, et al. Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci USA. 2010;107:6346–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Balaji K, Mooser C, Janson CM, Bliss JM, Hojjat H, Colicelli J. RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR. J Cell Sci. 2012;125:5887–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–30.

    PubMed  PubMed Central  Google Scholar 

  48. McMillan HJ, Telegrafi A, Singleton A, Cho MT, Lelli D, Lynn FC, et al. Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. Orphanet J Rare Dis. 2018;13:86.

    PubMed  PubMed Central  Google Scholar 

  49. Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65:45–53.

    PubMed  Google Scholar 

  50. Zhu X, Libby RT, de Vries WN, Smith RS, Wright DL, Bronson RT, et al. Mutations in a P-type ATPase gene cause axonal degeneration. PLoS Genet. 2012;8:e1002853.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Martin-Hernandez E, Rodriguez-Garcia ME, Camacho A, Matilla-Duenas A, Garcia-Silva MT, Quijada-Fraile P, et al. New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Neurogenetics. 2016;17:259–63.

    CAS  PubMed  Google Scholar 

  52. Kerr DJ, Marsillo A, Guariglia SR, Budylin T, Sadek R, Menkes S, et al. Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior. Biochim Biophys Acta. 2016;1862:1755–65.

    CAS  PubMed  Google Scholar 

  53. Padamsey Z, McGuinness L, Bardo SJ, Reinhart M, Tong R, Hedegaard A, et al. Activity-dependent exocytosis of lysosomes regulates the structural plasticity of dendritic spines. Neuron. 2017;93:132–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ilie A, Gao AY, Reid J, Boucher A, McEwan C, Barriere H, et al. A Christianson syndrome-linked deletion mutation ((287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. Mol Neurodegener. 2016;11:63.

    PubMed  PubMed Central  Google Scholar 

  55. Huang W, Liu Z, Yang F, Zhou H, Yong X, Yang X, et al. Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH. Proc Natl Acad Sci USA. 2019;116:22598–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184–91.

    CAS  PubMed  Google Scholar 

  57. Rocca DL, Amici M, Antoniou A, Blanco Suarez E, Halemani N, Murk K, et al. The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity. Neuron. 2013;79:293–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Trischler M, Stoorvogel W, Ullrich O. Biochemical analysis of distinct Rab5- and Rab11-positive endosomes along the transferrin pathway. J Cell Sci. 1999;112:4773–83.

    CAS  PubMed  Google Scholar 

  59. Moya-Alvarado G, Gonzalez A, Stuardo N, Bronfman FC. Brain-derived neurotrophic factor (BDNF) regulates Rab5-positive early endosomes in hippocampal neurons to induce dendritic branching. Front Cell Neurosci. 2018;12:493.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Brown TC, Correia SS, Petrok CN, Esteban JA. Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J Neurosci. 2007;27:13311–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Brown TC, Tran IC, Backos DS, Esteban JA. NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron. 2005;45:81–94.

    CAS  PubMed  Google Scholar 

  62. Chandran J, Ding J, Cai H. Alsin and the molecular pathways of amyotrophic lateral sclerosis. Mol Neurobiol. 2007;36:224–31.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the affected individuals and their parents for their participation in this study. We thank Dr. Qi-Ming Sun’s lab (Zhejiang University) for their assistance in the project.

Funding

National Natural Science Foundation of China 92254307, 91754115, and 32170758 (DF), National Natural Science Foundation of China 82001205 (TM), Natural Science Foundation of Guangdong 2020A1515010022 (TM), Fundamental and Applied Fundamental Research Project of Guangzhou 202102020016 (TM), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS, DF), Guangzhou Ling Nan Ying Cai Project 2018, Q847004 (DF).

Author information

Author notes

  1. These authors contributed equally: Tian Meng, Xiaoting Chen.

Authors and Affiliations

  1. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China

    Tian Meng, Xiaoting Chen, Zhengjie He, Haofeng Huang, Shiyin Lin, Kunru Liu, Guo Bai & Du Feng

  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China

    Tian Meng, Zhengjie He, Hao Liu & Du Feng

  3. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 511436, Guangzhou, China

    Tian Meng, Hao Liu & Du Feng

  4. Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511500, China

    Hao Liu

  5. Key Laboratory of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Mindong Xu, Yunlong Zhang & Xiang-Dong Sun

  6. Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China

    Haixia Zhuang & Huansen Huang

  7. Department of Zoology, Division of Science and Technology, University of Education, Lahore, 54000, Pakistan

    Ahmed Waqas

  8. Department of Cerebrovascular Disease Center, Gansu Provincial Hospital, Lanzhou, 730000, China

    Qian Liu

  9. Medical Genetics Center, Gansu Provincial Maternity and Child-care Hospital; Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou, 730050, China

    Chuan Zhang

  10. Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGH), Riyadh, 11481, Saudi Arabia

    Muhammad Umair

  11. Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, 22209, Pakistan

    Muhammad Umair

  12. Prenatal Diagnostic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China

    Yousheng Yan

Authors
  1. Tian Meng
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiaoting Chen
    View author publications

    Search author on:PubMed Google Scholar

  3. Zhengjie He
    View author publications

    Search author on:PubMed Google Scholar

  4. Haofeng Huang
    View author publications

    Search author on:PubMed Google Scholar

  5. Shiyin Lin
    View author publications

    Search author on:PubMed Google Scholar

  6. Kunru Liu
    View author publications

    Search author on:PubMed Google Scholar

  7. Guo Bai
    View author publications

    Search author on:PubMed Google Scholar

  8. Hao Liu
    View author publications

    Search author on:PubMed Google Scholar

  9. Mindong Xu
    View author publications

    Search author on:PubMed Google Scholar

  10. Haixia Zhuang
    View author publications

    Search author on:PubMed Google Scholar

  11. Yunlong Zhang
    View author publications

    Search author on:PubMed Google Scholar

  12. Ahmed Waqas
    View author publications

    Search author on:PubMed Google Scholar

  13. Qian Liu
    View author publications

    Search author on:PubMed Google Scholar

  14. Chuan Zhang
    View author publications

    Search author on:PubMed Google Scholar

  15. Xiang-Dong Sun
    View author publications

    Search author on:PubMed Google Scholar

  16. Huansen Huang
    View author publications

    Search author on:PubMed Google Scholar

  17. Muhammad Umair
    View author publications

    Search author on:PubMed Google Scholar

  18. Yousheng Yan
    View author publications

    Search author on:PubMed Google Scholar

  19. Du Feng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

TM, X-TC and DF conceived the study and prepared the figures and manuscript. Y-SY, MU, AW, QL and CZ contributed to the recruitment and characterization of the patients. TM, Z-JH, H-FH and S-YL performed the in vivo and in vitro experiments for phenotypic characterization. M-DX performed the electrophysiological recording of brain slices. K-RL, GB and H-XZ performed the biochemical experiments and bioinformatics analysis. X-DS, Y-LZ, H-SH and HL discussed and revised the manuscript. DF supervised the experiments and approved the manuscript.

Corresponding authors

Correspondence to Muhammad Umair, Yousheng Yan or Du Feng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meng, T., Chen, X., He, Z. et al. ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity. Mol Psychiatry 28, 1219–1231 (2023). https://doi.org/10.1038/s41380-022-01940-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-022-01940-w

This article is cited by

Search

Advanced search

Quick links