An inside job: How endosomal Na+ /H+ exchangers link to autism and neurological disease

Frontiers in Cellular Neuroscience

Volumn 8, Issue JUN, 2014, Pages

  Kondapalli, Kalyan C ^a   Prasad, Hari ^a   Rao, Rajini ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

ADHD; Autism; Christianson syndrome; Endosomes; SLC9A6; SLC9A9; Sodium proton exchanger; Trafficking

Indexed keywords

NEUROTRANSMITTER; PROTON; RECEPTOR FOR ACTIVATED C KINASE 1; SODIUM ION; SODIUM PROTON EXCHANGE PROTEIN;

ALZHEIMER DISEASE; ATTENTION DEFICIT DISORDER; AUTISM; CORTICOBASAL DEGENERATION; ENDOCYTOSIS; ENZYME ACTIVITY; EPILEPSY; GENE MUTATION; HAPPY PUPPET SYNDROME; HUMAN; MULTIPLE SCLEROSIS; NEUROLOGIC DISEASE; NONHUMAN; PHYLOGENY; REVIEW; SIGNAL TRANSDUCTION;

EID: 84923780866     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00172     Document Type: Review

References (148)

1. Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., Beechey, C. V., Armstrong, D., Eichele, G., et al. (1997). Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat. Genet. 17, 75-78. doi: 10.1038/ng0997-75
2. Ali, R., Brett, C. L., Mukherjee, S., and Rao, R. (2004). Inhibition of sodium/proton exchange by a Rab-GTPase-activating protein regulates endosomal traffic in yeast. J. Biol. Chem. 279, 4498-4506. doi: 10.1074/jbc.M307446200
3. Amr, M., Raddad, D., El-Mehesh, F., Bakr, A., Sallam, K., and Amin, T. (2012). Comorbid psychiatric disorders in Arab children with autism spectrum disorders. Res. Autism Spectr. Disord. 6, 240-248. doi: 10.1016/j.rasd.2011.05.005
4. Andres, Z., Perez-Hormaeche, J., Leidi, E. O., Schlucking, K., Steinhorst, L., Mclachlan, D. H., et al. (2014). Control of vacuolar dynamics and regulation of stomatal aperture by tonoplast potassium uptake. Proc. Natl. Acad. Sci. U.S.A. 111, E1806-E1814. doi: 10.1073/pnas.1320421111
5. Antshel, K. M., Zhang-James, Y., and Faraone, S. V. (2013). The comorbidity of ADHD and autism spectrum disorder. Expert Rev. Neurother. 13, 1117-1128. doi: 10.1586/14737175.2013.840417
6. Apse, M. P., Aharon, G. S., Snedden, W. A., and Blumwald, E. (1999). Salt tolerance conferred by overexpression of a vacuolar Na+/H+ antiport in Arabidopsis. Science 285, 1256-1258. doi: 10.1126/science.285.5431.1256
7. Araque, A., Parpura, V., Sanzgiri, R. P., and Haydon, P. G. (1999). Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208-215. doi: 10.1016/S0166-2236(98)01349-6
8. Arking, D. E., Cutler, D. J., Brune, C. W., Teslovich, T. M., West, K., Ikeda, M., et al. (2008). A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160-164. doi: 10.1016/j.ajhg.2007.09.015
9. Ashkenazy, H., Erez, E., Martz, E., Pupko, T., and Ben-Tal, N. (2010). ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res. 38(Suppl.), W529-W533. doi: 10.1093/nar/gkq399
10. Baio, J. (2014). Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR. Surveill. Summ. 63(Suppl. 2), 1-21. Available online at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6302a1.htm
11. Ben-David, E., Granot-Hershkovitz, E., Monderer-Rothkoff, G., Lerer, E., Levi, S., Yaari, M., et al. (2011). Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum. Mol. Genet. 20, 3632-3641. doi: 10.1093/hmg/ddr283
12. Blanpied, T. A., and Ehlers, M. D. (2011). Membrane trafficking and cytoskeletal dynamics in neuronal function. Mol. Cell. Neurosci. 48, 267-268. doi: 10.1016/j.mcn.2011.09.006
13. Blanpied, T. A., Kerr, J. M., and Ehlers, M. D. (2008). Structural plasticity with preserved topology in the postsynaptic protein network. Proc. Natl. Acad. Sci. U.S.A. 105, 12587-12592. doi: 10.1073/pnas.0711669105
14. Bosemani, T., Zanni, G., Hartman, A. L., Cohen, R., Huisman, T. A., Bertini, E., et al. (2013). Christianson syndrome: spectrum of neuroimaging findings. Neuropediatrics doi: 10.1055/s-0033-1363091. [Epub ahead of print].
15. Brett, C. L., Donowitz, M., and Rao, R. (2005a). Evolutionary origins of eukaryotic sodium/proton exchangers. Am. J. Physiol. Cell Physiol. 288, C223-C239. doi: 10.1152/ajpcell.00360.2004
16. Brett, C. L., Donowitz, M., and Rao, R. (2006). Does the proteome encode organellar pH? FEBS Lett. 580, 717-719. doi: 10.1016/j.febslet.2005.12.103
17. Brett, C. L., Kallay, L., Hua, Z., Green, R., Chyou, A., Zhang, Y., et al. (2011). Genome-wide analysis reveals the vacuolar pH-stat of Saccharomyces cerevisiae. PLoS ONE 6:e17619. doi: 10.1371/journal.pone.0017619
18. Brett, C. L., Tukaye, D. N., Mukherjee, S., and Rao, R. (2005b). The yeast endosomal Na+K+/H+ exchanger Nhx1 regulates cellular pH to control vesicle trafficking. Mol. Biol. Cell 16, 1396-1405. doi: 10.1091/mbc.E04-11-0999
19. Brett, C. L., Wei, Y., Donowitz, M., and Rao, R. (2002). Human Na(+)/H(+) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am. J. Physiol. Cell Physiol. 282, C1031-C1041. doi: 10.1152/ajpcell.00420.2001
20. Brookes, K., Xu, X., Chen, W., Zhou, K., Neale, B., Lowe, N., et al. (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. doi: 10.1038/sj.mp.4001869
21. Canitano, R. (2007). Epilepsy in autism spectrum disorders. Eur. Child Adolesc. Psychiatry 16, 61-66. doi: 10.1007/s00787-006-0563-2
22. Casey, J. R., Grinstein, S., and Orlowski, J. (2010). Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 11, 50-61. doi: 10.1038/nrm2820
23. Cha, B., and Donowitz, M. (2008). The epithelial brush border Na+/H+ exchanger NHE3 associates with the actin cytoskeleton by binding to ezrin directly and via PDZ domain-containing Na+/H+ exchanger regulatory factor (NHERF) proteins. Clin. Exp. Pharmacol. Physiol. 35, 863-871. doi: 10.1111/j.1440-1681.2008.04931.x
24. Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T., Qin, J., et al. (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224-1229. doi: 10.1126/science.1153252
25. Christianson, A. L., Stevenson, R. E., van der Meyden, C. H., Pelser, J., Theron, F. W., Van Rensburg, P. L., et al. (1999). X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J. Med. Genet. 36, 759-766. doi: 10.1136/jmg.36.10.759
26. Cosker, K. E., Courchesne, S. L., and Segal, R. A. (2008). Action in the axon: generation and transport of signaling endosomes. Curr. Opin. Neurobiol. 18, 270-275. doi: 10.1016/j.conb.2008.08.005
27. Cui, B., Wu, C., Chen, L., Ramirez, A., Bearer, E. L., Li, W. P., et al. (2007). One at a time, live tracking of NGF axonal transport using quantum dots. Proc. Natl. Acad. Sci. U.S.A. 104, 13666-13671. doi: 10.1073/pnas.0706192104
28. da Silva, S., and Wang, F. (2011). Retrograde neural circuit specification by target-derived neurotrophins and growth factors. Curr. Opin. Neurobiol. 21, 61-67. doi: 10.1016/j.conb.2010.07.007
29. Deane, E. C., Ilie, A. E., Sizdahkhani, S., Das Gupta, M., Orlowski, J., and McKinney, R. A. (2013). Enhanced recruitment of endosomal Na+/H+ exchanger NHE6 into dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. J. Neurosci. 33, 595-610. doi: 10.1523/JNEUROSCI.2583-12.2013
30. Deinhardt, K., Salinas, S., Verastegui, C., Watson, R., Worth, D., Hanrahan, S., et al. (2006). Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293-305. doi: 10.1016/j.neuron.2006.08.018
31. Delcroix, J. D., Valletta, J. S., Wu, C., Hunt, S. J., Kowal, A. S., and Mobley, W. C. (2003). NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39, 69-84. doi: 10.1016/S0896-6273(03)00397-0
32. Delorme, R., Ey, E., Toro, R., Leboyer, M., Gillberg, C., and Bourgeron, T. (2013). Progress toward treatments for synaptic defects in autism. Nat. Med. 19, 685-694. doi: 10.1038/nm.3193
33. de Silva, M. G., Elliott, K., Dahl, H. H., Fitzpatrick, E., Wilcox, S., Delatycki, M., et al. (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. doi: 10.1136/jmg.40.10.733
34. Devlin, B., and Scherer, S. W. (2012). Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22, 229-237. doi: 10.1016/j.gde.2012.03.002
35. Di Giovanni, J., Boudkkazi, S., Mochida, S., Bialowas, A., Samari, N., Leveque, C., et al. (2010). V-ATPase membrane sector associates with synaptobrevin to modulate neurotransmitter release. Neuron 67, 268-279. doi: 10.1016/j.neuron.2010.06.024
36. Donowitz, M., Ming Tse, C., and Fuster, D. (2013). SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol. Aspects Med. 34, 236-251. doi: 10.1016/j.mam.2012.05.001
37. Edwards, R. H. (2007). The neurotransmitter cycle and quantal size. Neuron 55, 835-858. doi: 10.1016/j.neuron.2007.09.001
38. Esposito, F., Sorosina, M., Lim, E., Brambilla, P., Romeo, M., Rodegher, M., et al. (2013). An SLC9A9 variant influences treatment response in interferon beta treated multiple sclerosis patients. Neurology 80, 1. Available online at: http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P05.141
39. Faraone, S. V., and 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. 162, 711-717. doi: 10.1002/ajmg.b.32155
40. Farley, M. A., McMahon, W. M., Fombonne, E., Jenson, W. R., Miller, J., Gardner, M., et al. (2009). Twenty-year outcome for individuals with autism and average or near-average cognitive abilities. Autism Res. 2, 109-118. doi: 10.1002/aur.69
41. Fichou, Y., Bahi-Buisson, N., Nectoux, J., Chelly, J., Heron, D., Cuisset, L., et al. (2009). Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome. Eur. J. Hum. Genet. 17, 1378-1380. doi: 10.1038/ejhg.2009.82
42. Fisher, S. E., Francks, C., McCracken, J. T., McGough, J. J., Marlow, A. J., MacPhie, I. L., et al. (2002). A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. 70, 1183-1196. doi: 10.1086/340112
43. Flavell, S. W., and Greenberg, M. E. (2008). Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563-590. doi: 10.1146/annurev.neuro.31.060407.125631
44. Flavell, S. W., Kim, T. K., Gray, J. M., Harmin, D. A., Hemberg, M., Hong, E. J., et al. (2008). Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022-1038. doi: 10.1016/j.neuron.2008.11.029
45. Folstein, S. E., and Rosen-Sheidley, B. (2001). Genetics of autism: complex aetiology for a heterogeneous disorder. Nat. Rev. Genet. 2, 943-955. doi: 10.1038/35103559
46. Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: an update. J. Autism Dev. Disord. 33, 365-382. doi: 10.1023/A:1025054610557
47. Fukada-Tanaka, S., Inagaki, Y., Yamaguchi, T., Saito, N., and Iida, S. (2000). Colour-enhancing protein in blue petals. Nature 407, 581. doi: 10.1038/35036683
48. Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M., Feldman, G., Norris, J. W., et al. (2010). A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 133, 1391-1402. doi: 10.1093/brain/awq071
49. Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., et al. (2008). SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am. J. Hum. Genet. 82, 1003-1010. doi: 10.1016/j.ajhg.2008.01.013
50. Gjevik, E., Eldevik, S., Fjaeran-Granum, T., and Sponheim, E. (2011). Kiddie-SADS reveals high rates of DSM-IV disorders in children and adolescents with autism spectrum disorders. J. Autism Dev. Disord. 41, 761-769. doi: 10.1007/s10803-010-1095-7
51. Goh, G. Y., Huang, H., Ullman, J., Borre, L., Hnasko, T. S., Trussell, L. O., et al. (2011). Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport. Nat. Neurosci. 14, 1285-1292. doi: 10.1038/nn.2898
52. Gronborg, M., Pavlos, N. J., Brunk, I., Chua, J. J., Munster-Wandowski, A., Riedel, D., et al. (2010). Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein. J. Neurosci. 30, 2-12. doi: 10.1523/JNEUROSCI.4074-09.2010
53. Gundelfinger, E. D., Kessels, M. M., and Qualmann, B. (2003). Temporal and spatial coordination of exocytosis and endocytosis. Nat. Rev. Mol. Cell Biol. 4, 127-139. doi: 10.1038/nrm1016
54. Guterman, M. (2013). NHE6 and NHE9 are Sodium Hydrogen Exchangers Found on Separate Mobile Endosome Populations in Neuronal Dendrites. Masters thesis, Concordia University, Montreal, QC.
55. Han, W., Kim, K. H., Jo, M. J., Lee, J. H., Yang, J., Doctor, R. B., et al. (2006). Shank2 associates with and regulates Na+/H+ exchanger 3. J. Biol. Chem. 281, 1461-1469. doi: 10.1074/jbc.M509786200
56. Hannah, M. J., Schmidt, A. A., and Huttner, W. B. (1999). Synaptic vesicle biogenesis. Annu. Rev. Cell Dev. Biol. 15, 733-798. doi: 10.1146/annurev.cellbio.15.1.733
57. Hill, J. K., Brett, C. L., Chyou, A., Kallay, L. M., Sakaguchi, M., Rao, R., et al. (2006). Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9. J. Neurosci. 26, 9944-9955. doi: 10.1523/JNEUROSCI.2990-06.2006
58. Howlin, P., Goode, S., Hutton, J., and Rutter, M. (2004). Adult outcome for children with autism. J. Child Psychol. Psychiatry 45, 212-229. doi: 10.1111/j.1469-7610.2004.00215.x
59. Howlin, P., Mawhood, L., and Rutter, M. (2000). Autism and developmental receptive language disorder-a follow-up comparison in early adult life. II: social, behavioural, and psychiatric outcomes. J. Child Psychol. Psychiatry 41, 561-578. doi: 10.1111/1469-7610.00643
60. Huffman, J. E., Knezevic, A., Vitart, V., Kattla, J., Adamczyk, B., Novokmet, M., et al. (2011). Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults. Hum. Mol. Genet. 20, 5000-5011. doi: 10.1093/hmg/ddr414
61. Hunte, C., Screpanti, E., Venturi, M., Rimon, A., Padan, E., and Michel, H. (2005). Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature 435, 1197-1202. doi: 10.1038/nature03692
62. Hurtado-Lorenzo, A., Skinner, M., El Annan, J., Futai, M., Sun-Wada, G. H., Bourgoin, S., et al. (2006). V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat. Cell Biol. 8, 124-136. doi: 10.1038/ncb1348
63. Hu, H., Wrogemann, K., Kalscheuer, V., Tzschach, A., Richard, H., Haas, S. A., et al. (2009). Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing. Hugo. J. 3, 41-49. doi: 10.1007/s11568-010-9137-y
64. Ilie, A., Weinstein, E., Boucher, A., McKinney, R. A., and Orlowski, J. (2013). Impaired posttranslational processing and trafficking of an endosomal Na/H exchanger NHE6 mutant (DeltaWST) associated with X-linked intellectual disability and autism. Neurochem. Int. doi: 10.1016/j.neuint.2013.09.020. [Epub ahead of print].
65. Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., et al. (2012). De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285-299. doi: 10.1016/j.neuron.2012.04.009
66. Jozwiak, S., Kotulska, K., Domanska-Pakiela, D., Lojszczyk, B., Syczewska, M., Chmielewski, D., et al. (2011). Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 15, 424-431. doi: 10.1016/j.ejpn.2011.03.010
67. Kallay, L. M., Brett, C. L., Tukaye, D. N., Wemmer, M. A., Chyou, A., Odorizzi, G., et al. (2011). Endosomal Na+ (K+)/H+ exchanger Nhx1/Vps44 functions independently and downstream of multivesicular body formation. J. Biol. Chem. 286, 44067-44077. doi: 10.1074/jbc.M111.282319
68. Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child 2, 217-250.
69. Kantheti, P., Qiao, X., Diaz, M. E., Peden, A. A., Meyer, G. E., Carskadon, S. L., et al. (1998). Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21, 111-122. doi: 10.1016/S0896-6273(00)80519-X
70. Kondapalli, K. C., Hack, A., Schushan, M., Landau, M., Ben-Tal, N., and Rao, R. (2013). Functional evaluation of autism-associated mutations in NHE9. Nat. Commun. 4, 2510. doi: 10.1038/ncomms3510
71. Konopka, G., Wexler, E., Rosen, E., Mukamel, Z., Osborn, G. E., Chen, L., et al. (2012). Modeling the functional genomics of autism using human neurons. Mol. Psychiatry 17, 202-214. doi: 10.1038/mp.2011.60
72. Landau, M., Herz, K., Padan, E., and Ben-Tal, N. (2007). Model structure of the Na+/H+ exchanger 1 (NHE1): functional and clinical implications. J. Biol. Chem. 282, 37854-37863. doi: 10.1074/jbc.M705460200
73. Landrigan, P. J. (2010). What causes autism? Exploring the environmental contribution. Curr. Opin. Pediatr. 22, 219-225. doi: 10.1097/MOP.0b013e328336eb9a
74. Lasky-Su, J., Neale, B. M., Franke, B., Anney, R. J., Zhou, K., Maller, J. B., et al. (2008). 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. doi: 10.1002/ajmg.b.30867
75. Lawson-Yuen, A., Saldivar, J. S., Sommer, S., and Picker, J. (2008). Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur. J. Hum. Genet. 16, 614-618. doi: 10.1038/sj.ejhg.5202006
76. Lee, C., Kang, H. J., von Ballmoos, C., Newstead, S., Uzdavinys, P., Dotson, D. L., et al. (2013). A two-domain elevator mechanism for sodium/proton antiport. Nature 501, 573-577. doi: 10.1038/nature12484
77. Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., et al. (2007). Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168-176. doi: 10.1038/nature05453
78. Lin, X., and Barber, D. L. (1996). A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange. Proc. Natl. Acad. Sci. U.S.A. 93, 12631-12636. doi: 10.1073/pnas.93.22.12631
79. Liu, X. Q., Paterson, A. D., and Szatmari, P. (2008). Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol. Psychiatry 64, 561-570. doi: 10.1016/j.biopsych.2008.05.023
80. Madrigal, I., Fernandez-Burriel, M., Rodriguez-Revenga, L., Cabrera, J. C., Marti, M., Mur, A., et al. (2010). Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization. J. Hum. Genet. 55, 822-826. doi: 10.1038/jhg.2010.119
81. Markunas, C. A., Quinn, K. S., Collins, A. L., Garrett, M. E., Lachiewicz, A. M., Sommer, J. L., et al. (2010). Genetic variants in SLC9A9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families. Psychiatr. Genet. 20, 73-81. doi: 10.1097/YPG.0b013e3283351209
82. Martineau, M., Shi, T., Puyal, J., Knolhoff, A. M., Dulong, J., Gasnier, B., et al. (2013). Storage and uptake of D-serine into astrocytic synaptic-like vesicles specify gliotransmission. J. Neurosci. 33, 3413-3423. doi: 10.1523/JNEUROSCI.3497-12.2013
83. Martinelli-Boneschi, F., Giacalone, G., Magnani, G., Biella, G., Coppi, E., Santangelo, R., et al. (2013). Pharmacogenomics in Alzheimer's disease: a genome-wide association study of response to cholinesterase inhibitors. Neurobiol. Aging 34, 1711. e7-1711. e13. doi: 10.1016/j.neurobiolaging.2012.12.008
84. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C., and Kasai, H. (2004). Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761-766. doi: 10.1038/nature02617
85. Mellman, I. (1992). The importance of being acid: the role of acidification in intracellular membrane traffic. J. Exp. Biol. 172, 39-45.
86. Mick, E., Todorov, A., Smalley, S., Hu, X., Loo, S., Todd, R. D., et al. (2010). Family-based genome-wide association scan of attention-deficit/hyperactivity disorder. J. Am. Acad. Child. Adolesc. Psychiatry. 49, 898-905. e3. doi: 10.1016/j.jaac.2010.02.014
87. Mignot, C., Heron, D., Bursztyn, J., Momtchilova, M., Mayer, M., Whalen, S., et al. (2013). Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain Dev. 35, 172-176. doi: 10.1016/j.braindev.2012.03.010
88. Mitchell, S. R., Reiss, A. L., Tatusko, D. H., Ikuta, I., Kazmerski, D. B., Botti, J. A., et al. (2009). Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder. Am. J. Psychiatry 166, 917-925. doi: 10.1176/appi.ajp.2009.08101538
89. Mkhikian, H., Grigorian, A., Li, C. F., Chen, H. L., Newton, B., Zhou, R. W., et al. (2011). Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat. Commun. 2, 334. doi: 10.1038/ncomms1333
90. Molofsky, A. V., Krencik, R., Ullian, E. M., Tsai, H. H., Deneen, B., Richardson, W. D., et al. (2012). Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 26, 891-907. doi: 10.1101/gad.188326.112
91. Montana, V., Ni, Y., Sunjara, V., Hua, X., and Parpura, V. (2004). Vesicular glutamate transporter-dependent glutamate release from astrocytes. J. Neurosci. 24, 2633-2642. doi: 10.1523/JNEUROSCI.3770-03.2004
92. Morel, N., Dedieu, J. C., and Philippe, J. M. (2003). Specific sorting of the a1 isoform of the V-H+ATPase a subunit to nerve terminals where it associates with both synaptic vesicles and the presynaptic plasma membrane. J. Cell Sci. 116, 4751-4762. doi: 10.1242/jcs.00791
93. Morrow, E. M., Yoo, S. Y., Flavell, S. W., Kim, T. K., Lin, Y., Hill, R. S., et al. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218-223. doi: 10.1126/science.1157657
94. Muro, S., Garnacho, C., Champion, J. A., Leferovich, J., Gajewski, C., Schuchman, E. H., et al. (2008). Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers. Mol. Ther. 16, 1450-1458. doi: 10.1038/mt.2008.127
95. Murthy, V. N., and De Camilli, P. (2003). Cell biology of the presynaptic terminal. Annu. Rev. Neurosci. 26, 701-728. doi: 10.1146/annurev.neuro.26.041002.131445
96. Musgrove, E., Seaman, M., and Hedley, D. (1987). Relationship between cytoplasmic pH and proliferation during exponential growth and cellular quiescence. Exp. Cell Res. 172, 65-75. doi: 10.1016/0014-4827(87)90093-0
97. Nakamura, N., Tanaka, S., Teko, Y., Mitsui, K., and 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. doi: 10.1074/jbc.M410041200
98. Nishiguchi, M., Tokugawa, K., Yamamoto, K., Akama, T., Nozawa, Y., Chaki, S., et al. (2003). Increase in secretion of glial cell line-derived neurotrophic factor from glial cell lines by inhibitors of vacuolar ATPase. Neurochem. Int. 42, 493-498. doi: 10.1016/S0197-0186(02)00139-0
99. Ohgaki, R., Fukura, N., Matsushita, M., Mitsui, K., and 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. doi: 10.1074/jbc.M705146200
100. Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., and van Ijzendoorn, S. C. (2010). The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells. Mol. Biol. Cell 21, 1293-1304. doi: 10.1091/mbc.E09-09-0767
101. Ohgaki, R., Van, I. S. C., Matsushita, M., Hoekstra, D., and Kanazawa, H. (2011). Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50, 443-450. doi: 10.1021/bi101082e
102. Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., et al. (2013). Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron 80, 97-112. doi: 10.1016/j.neuron.2013.07.043
103. Paradiso, A., Cardone, R. A., Bellizzi, A., Bagorda, A., Guerra, L., Tommasino, M., et al. (2004). The Na+-H+ exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells. Breast Cancer Res. 6, R616-R628. doi: 10.1186/bcr922
104. Pardo, J. M., Cubero, B., Leidi, E. O., and Quintero, F. J. (2006). Alkali cation exchangers: roles in cellular homeostasis and stress tolerance. J. Exp. Bot. 57, 1181-1199. doi: 10.1093/jxb/erj114
105. Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A., and Ehlers, M. D. (2004). Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972-1975. doi: 10.1126/science.1102026
106. Parpura, V., and Zorec, R. (2010). Gliotransmission: exocytotic release from astrocytes. Brain Res. Rev. 63, 83-92. doi: 10.1016/j.brainresrev.2009.11.008
107. Perez-Palma, E., Bustos, B. I., Villaman, C. F., Alarcon, M. A., Avila, M. E., Ugarte, G. D., et al. (2014). Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies. PLoS ONE 9:e95413. doi: 10.1371/journal.pone.0095413
108. Pescosolido, M. F., Yang, U., Sabbagh, M., and Morrow, E. M. (2012). Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders. Dialogues Clin. Neurosci. 14, 239-252. Available online at: http://www.dialogues-cns.org/publication/lighting-a-path-genetic-studies-pinpoint-neurodevelopmental-mechanisms-in-autism-and-related-disorders/
109. Peters, S. U., Hundley, R. J., Wilson, A. K., Warren, Z., Vehorn, A., Carvalho, C. M., et al. (2013). The behavioral phenotype in MECP2 duplication syndrome: a comparison with idiopathic autism. Autism Res. 6, 42-50. doi: 10.1002/aur.1262
110. Piton, A., Gauthier, J., Hamdan, F. F., Lafreniere, R. G., Yang, Y., Henrion, E., et al. (2011). Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol. Psychiatry 16, 867-880. doi: 10.1038/mp.2010.54
111. Piton, A., Redin, C., and Mandel, J. L. (2013). XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am. J. Hum. Genet. 93, 368-383. doi: 10.1016/j.ajhg.2013.06.013
112. Pulakat, L., Cooper, S., Knowle, D., Mandavia, C., Bruhl, S., Hetrick, M., et al. (2005). Ligand-dependent complex formation between the Angiotensin II receptor subtype AT2 and Na+/H+ exchanger NHE6 in mammalian cells. Peptides 26, 863-873. doi: 10.1016/j.peptides.2004.12.015
113. Riess, A., Rossier, E., Kruger, R., Dufke, A., Beck-Woedl, S., Horber, V., et al. (2013). Novel SLC9A6 mutations in two families with Christianson syndrome. Clin. Genet. 83, 596-597. doi: 10.1111/j.1399-0004.2012.01948.x
114. Rink, J., Ghigo, E., Kalaidzidis, Y., and Zerial, M. (2005). Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735-749. doi: 10.1016/j.cell.2005.06.043
115. Roxrud, I., Raiborg, C., Gilfillan, G. D., Stromme, P., and Stenmark, H. (2009). Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease. Exp. Cell Res. 315, 3014-3027. doi: 10.1016/j.yexcr.2009.07.012
116. Santangelo, S. L., and Tsatsanis, K. (2005). What is known about autism: genes, brain, and behavior. Am. J. Pharmacogenomics 5, 71-92. doi: 10.2165/00129785-200505020-00001
117. Santoni, F. A., Makrythanasis, P., Nikolaev, S., Guipponi, M., Robyr, D., Bottani, A., et al. (2014). Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster. Genome Res. 24, 349-355. doi: 10.1101/gr.163832.113
118. Schroer, R. J., Holden, K. R., Tarpey, P. S., Matheus, M. G., Griesemer, D. A., Friez, M. J., et al. (2010). Natural history of Christianson syndrome. Am. J. Med. Genet. A 152A, 2775-2783. doi: 10.1002/ajmg.a.33093
119. Schuurs-Hoeijmakers, J. H., Vulto-van Silfhout, A. T., Vissers, L. E., van de Vondervoort, I. I., van Bon, B. W., de Ligt, J., et al. (2013). Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. J. Med. Genet. 50, 802-811. doi: 10.1136/jmedgenet-2013-101644
120. Schwede, M., Garbett, K., Mirnics, K., Geschwind, D. H., and Morrow, E. M. (2014). Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol. Psychiatry. 19, 277-279. doi: 10.1038/mp.2013.28
121. Seltzer, L. E., and Paciorkowski, A. R. (2014). Genetic disorders associated with postnatal microcephaly. Am. J. Med. Genet. C Semin. Med. Genet. doi: 10.1002/ajmg.c.31400. [Epub ahead of print].
122. Seltzer, M. M., Shattuck, P., Abbeduto, L., and Greenberg, J. S. (2004). Trajectory of development in adolescents and adults with autism. Ment. Retard. Dev. Disabil. Res. Rev. 10, 234-247. doi: 10.1002/mrdd.20038
123. Smith, S. J. (1994). Neural signalling. Neuromodulatory astrocytes. Curr. Biol. 4, 807-810. doi: 10.1016/S0960-9822(00)00178-0
124. Somjen, G. G. (1984). Acidification of interstitial fluid in hippocampal formation caused by seizures and by spreading depression. Brain Res. 311, 186-188. doi: 10.1016/0006-8993(84)91416-1
125. Stromme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M., Ali, N. F., Davidson, C., et al. (2011). X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 134, 3369-3383. doi: 10.1093/brain/awr250
126. Sudhof, T. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903-911. doi: 10.1038/nature07456
127. Sudhof, T. C. (2012). The presynaptic active zone. Neuron 75, 11-25. doi: 10.1016/j.neuron.2012.06.012
128. Sunkin, S. M., Ng, L., Lau, C., Dolbeare, T., Gilbert, T. L., Thompson, C. L., et al. (2013). Allen brain atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res. 41, D996-D1008. doi: 10.1093/nar/gks1042
129. Takahashi, Y., Hosoki, K., Matsushita, M., Funatsuka, M., Saito, K., Kanazawa, H., Goto, Y., and Saitoh, S. (2011). A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156B, 799-807. doi: 10.1002/ajmg.b.31221
130. Takeshita, E., Nakagawa, E., Nakatani, K., Sasaki, M., and Goto, Y. (2012). Novel AGTR2 missense mutation in a Japanese boy with severe mental retardation, pervasive developmental disorder, and epilepsy. Brain Dev. 34, 776-779. doi: 10.1016/j.braindev.2011.12.010
131. Tan, W. H., Bird, L. M., Thibert, R. L., and Williams, C. A. (2014). If not Angelman, what is it? A review of Angelman-like syndromes. Am. J. Med. Genet. A 164A, 975-992. doi: 10.1002/ajmg.a.36416
132. Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., et al. (2009). A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat. Genet. 41, 535-543. doi: 10.1038/ng.367
133. Tzschach, A., Ullmann, R., Ahmed, A., Martin, T., Weber, G., Decker-Schwering, O., et al. (2011). Christianson syndrome in a patient with an interstitial Xq26.3 deletion. Am. J. Med. Genet. A 155A, 2771-2774. doi: 10.1002/ajmg.a.34230
134. Valapala, M., Hose, S., Gongora, C., Dong, L., Wawrousek, E. F., Samuel Zigler, J., et al. (2013). Impaired endolysosomal function disrupts notch signalling in optic nerve astrocytes. Nat. Commun. 4, 1629. doi: 10.1038/ncomms2624
135. van Loo, K. M., and Martens, G. J. (2007). Genetic and environmental factors in complex neurodevelopmental disorders. Curr. Genomics 8, 429-444. doi: 10.2174/138920207783591717
136. Vardarajan, B. N., Eran, A., Jung, J. Y., Kunkel, L. M., and Wall, D. P. (2013). Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder. Transl. Psychiatry 3, e262. doi: 10.1038/tp.2013.38
137. Vervoort, V. S., Beachem, M. A., Edwards, P. S., Ladd, S., Miller, K. E., de Mollerat, X., et al. (2002). AGTR2 mutations in X-linked mental retardation. Science 296, 2401-2403. doi: 10.1126/science.1072191
138. Vink, J. M., Smit, A. B., de Geus, E. J., Sullivan, P., Willemsen, G., Hottenga, J. J., et al. (2009). Genome-wide association study of smoking initiation and current smoking. Am. J. Hum. Genet. 84, 367-379. doi: 10.1016/j.ajhg.2009.02.001
139. Wagle, M., and Holder, J. (2014). Exonic deletion of SLC9A9 in autism with epilepsy. Neurology 82:P4.338. Available online at: http://www.neurology.org/content/82/10_Supplement/P4.338
140. Wang, J. C., Foroud, T., Hinrichs, A. L., Le, N. X., Bertelsen, S., Budde, J. P., et al. (2013). A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. Mol. Psychiatry 18, 1218-1224. doi: 10.1038/mp.2012.143
141. Whibley, A. C., Plagnol, V., Tarpey, P. S., Abidi, F., Fullston, T., Choma, M. K., et al. (2010). Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability. Am. J. Hum. Genet. 87, 173-188. doi: 10.1016/j.ajhg.2010.06.017
142. Williams, C. A., Lossie, A., and Driscoll, D. (2001). Angelman syndrome: mimicking conditions and phenotypes. Am. J. Med. Genet. 101, 59-64. doi: 10.1002/ajmg.1316
143. Xinhan, L., Matsushita, M., Numaza, M., Taguchi, A., Mitsui, K., and Kanazawa, H. (2011). Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am. J. Physiol. Cell Physiol. 301, C1431-C1444. doi: 10.1152/ajpcell.00154.2011
144. Xu, L. M., Li, J. R., Huang, Y., Zhao, M., Tang, X., and Wei, L. (2012). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic Acids Res. 40, D1016-D1022. doi: 10.1093/nar/gkr1145
145. Zanni, G., Barresi, S., Cohen, R., Specchio, N., Basel-Vanagaite, L., Valente, E. M., et al. (2014). A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Epilepsy Res. 108, 811-815. doi: 10.1016/j.eplepsyres.2014.02.009
146. Zerial, M., and McBride, H. (2001). Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol. 2, 107-117. doi: 10.1038/35052055
147. Zhang-James, Y., Dasbanerjee, T., Sagvolden, T., Middleton, F. A., and Faraone, S. V. (2011). SLC9A9 mutations, gene expression, and protein-protein interactions in rat models of attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 835-843. doi: 10.1002/ajmg.b.31229
148. Zhang-James, Y., Middleton, F. A., Sagvolden, T., and Faraone, S. V. (2012). Differential expression of SLC9A9 and interacting molecules in the hippocampus of rat models for attention deficit/hyperactivity disorder. Dev. Neurosci. 34, 218-227. doi: 10.1159/000338813