Molecular Neurobiology

, Volume 44, Issue 1, pp 83–92 | Cite as

The Mitochondrial Aspartate/Glutamate Carrier AGC1 and Calcium Homeostasis: Physiological Links and Abnormalities in Autism

  • Valerio Napolioni
  • Antonio M. Persico
  • Vito Porcelli
  • Luigi Palmieri


Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and behaviors. Recent evidence has unveiled an important role for calcium (Ca2+) signaling in the pathogenesis of ASD. Post-mortem studies of autistic brains have pointed toward abnormalities in mitochondrial function as possible downstream consequences of altered Ca2+ signaling, abnormal synapse formation, and dysreactive immunity. SLC25A12, an ASD susceptibility gene, encodes the Ca2+-regulated mitochondrial aspartate–glutamate carrier, isoform 1 (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate (ATP) production. Here, we review the physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis.


Aspartate–glutamate carrier Autism Autistic disorder Calcium signaling Mitochondria SLC25A12 



We gratefully acknowledge the Maryland NICHD Brain & Tissue Bank for Developmental Disorders, the Harvard Brain Tissue Resource Center, and the Autism Tissue Program for providing the brain tissue samples assessed in our studies. The Persico Lab is supported by the Italian Ministry for University, Scientific Research and Technology (PRIN n. 2006058195 and 2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174), the Autism Speaks Foundation (Princeton, NJ), the Autism Research Institute (San Diego, CA), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), and Autism Aids Onlus (Naples, Italy). The Palmieri lab is supported by the Italian Ministry for University, Scientific Research and Technology (PRIN n. 2008BACT54_002 and FIRB n. RBIN04PHZ7_001).

Conflict of Interest

We declare no conflict of interest.


  1. 1.
    Rimessi A, Giorgi C, Pinton P, Rizzuto R (2008) The versatility of mitochondrial calcium signals: from stimulation of cell metabolism to induction of cell death. Biochim Biophys Acta 1777:808–816PubMedCrossRefGoogle Scholar
  2. 2.
    Gunter KK, Gunter TE (1994) Transport of calcium by mitochondria. J Bioenerg Biomembr 26:471–485PubMedCrossRefGoogle Scholar
  3. 3.
    Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD (2004) Calcium and mitochondria. FEBS Lett 567:96–102PubMedCrossRefGoogle Scholar
  4. 4.
    Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364PubMedCrossRefGoogle Scholar
  5. 5.
    McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425PubMedGoogle Scholar
  6. 6.
    Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34:1259–1271PubMedCrossRefGoogle Scholar
  7. 7.
    Wernette ME, Ochs RS, Lardy HA (1981) Ca2+ stimulation of rat liver mitochondrial glycerophosphate dehydrogenase. J Biol Chem 256:12767–12771PubMedGoogle Scholar
  8. 8.
    Rutter GA, Pralong WF, Wollheim CB (1992) Regulation of mitochondrial glycerol-phosphate dehydrogenase by Ca2+ within electropermeabilized insulin-secreting cells (INS-1). Biochim Biophys Acta 1175:107–113PubMedCrossRefGoogle Scholar
  9. 9.
    MacDonald MJ, Brown LJ (1996) Calcium activation of mitochondrial glycerol phosphate dehydrogenase restudied. Arch Biochem Biophys 326:79–84PubMedCrossRefGoogle Scholar
  10. 10.
    Celsi F, Pizzo P, Brini M, Leo S, Fotino C, Pinton P, Rizzuto R (2009) Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta 1787:335–344PubMedCrossRefGoogle Scholar
  11. 11.
    Krey JF, Dolmetsch RE (2007) Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 17:112–119PubMedCrossRefGoogle Scholar
  12. 12.
    Palmieri L, Persico AM (2010) Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta 1797:1130–1137PubMedCrossRefGoogle Scholar
  13. 13.
    Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrústegui J, Palmieri F (2001) Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20:5060–5069PubMedCrossRefGoogle Scholar
  14. 14.
    Del Arco A, Morcillo J, Martínez-Morales JR, Galián C, Martos V, Bovolenta P, Satrústegui J (2002) Expression of the aspartate/glutamate mitochondrial carriers aralar1 and citrin during development and in adult rat tissues. Eur J Biochem 269:3313–3320PubMedCrossRefGoogle Scholar
  15. 15.
    Contreras L, Urbieta A, Kobayashi K, Saheki T, Satrústegui J (2010) Low levels of citrin (SLC25A13) expression in adult mouse brain restricted to neuronal clusters. J Neurosci Res 88:1009–1016PubMedGoogle Scholar
  16. 16.
    Del Arco A, Satrústegui J (1998) Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. J Biol Chem 273:23327–23334PubMedCrossRefGoogle Scholar
  17. 17.
    Lasorsa FM, Pinton P, Palmieri L, Fiermonte G, Rizzuto R, Palmieri F (2003) Recombinant expression of the Ca(2+)-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. J Biol Chem 278:38686–38692PubMedCrossRefGoogle Scholar
  18. 18.
    Palmieri F (2004) The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch 447:689–709PubMedCrossRefGoogle Scholar
  19. 19.
    Borst P (1963) Functionelle und Morphologische Organisation der Zelle. In: Karlson P (ed). Springer, BerlinGoogle Scholar
  20. 20.
    Sadava D, Depper M, Gilbert M, Bernard B, McCabe ER (1987) Development of enzymes of glycerol metabolism in human fetal liver. Biol Neonate 52:26–32PubMedCrossRefGoogle Scholar
  21. 21.
    Taylor WT, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS (2003) Characterization of the human heart mitochondrial proteome. Nat Biotechnol 21:281–286PubMedCrossRefGoogle Scholar
  22. 22.
    Scholz TD, Koppenhafer SL (1995) Reducing equivalent shuttles in developing porcine myocardium: enhanced capacity in the newborn heart. Pediatr Res 38:221–227PubMedCrossRefGoogle Scholar
  23. 23.
    Scholz TD, Koppenhafer SL, tenEyck CJ, Schutte BC (1998) Ontogeny of malate–aspartate shuttle capacity and gene expression in cardiac mitochondria. Am J Physiol Cell Physiol 274:780–788Google Scholar
  24. 24.
    Bassani RA, Fagian MM, Bassani JW, Vercesi AE (1998) Changes in calcium uptake rate by rat cardiac mitochondria during postnatal development. J Mol Cell Cardiol 30:2013–2023PubMedCrossRefGoogle Scholar
  25. 25.
    Begum L, Jalil MA, Kobayashi K, Iijima M, Li MX, Yasuda T, Horiuchi M, del Arco A, Satrustegui J, Saheki T (2002) Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice. Biochim Biophys Acta 1574:283–292PubMedGoogle Scholar
  26. 26.
    Dukes ID, McIntyre MS, Mertz RJ, Philipson LH, Roe MW, Spencer B, Worley JF 3rd (1994) Dependence on NADH produced during glycolysis for beta-cell glucose signaling. J Biol Chem 269:10979–10982PubMedGoogle Scholar
  27. 27.
    Giroix MH, Rasschaert J, Bailbe D, Leclercq-Meyer V, Sener A, Portha B, Malaisse WJ (1991) Impairment of glycerol phosphate shuttle in islets from rats with diabetes induced by neonatal streptozocin. Diabetes 40:227–232PubMedCrossRefGoogle Scholar
  28. 28.
    Tan C, Tuch BE, Tu J, Brown SA (2002) Role of NADH shuttles in glucose-induced insulin secretion from fetal beta-cells. Diabetes 51:2989–2996PubMedCrossRefGoogle Scholar
  29. 29.
    Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T (1999) Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 283:981–985PubMedCrossRefGoogle Scholar
  30. 30.
    Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P (2004) The malate–aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells. J Biol Chem 279:55659–55666PubMedCrossRefGoogle Scholar
  31. 31.
    Mármol P, Pardo B, Wiederkehr A, del Arco A, Wollheim CB, Satrústegui J (2009) Requirement for aralar and its Ca2+-binding sites in Ca2+ signal transduction in mitochondria from INS-1 clonal beta-cells. J Biol Chem 284:515–524PubMedCrossRefGoogle Scholar
  32. 32.
    Lane M, Gardner DK (2000) Lactate regulates pyruvate uptake and metabolism in the preimplantation mouse embryo. Biol Reprod 62:16–22PubMedCrossRefGoogle Scholar
  33. 33.
    Lane M, Gardner DK (2005) Mitochondrial malate–aspartate shuttle regulates mouse embryo nutrient consumption. J Biol Chem 280:18361–18367PubMedCrossRefGoogle Scholar
  34. 34.
    Ramos M, del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K, Yasuda T, Bogonez E, Bovolenta P, Saheki T, Satrùstegui J (2003) Developmental changes in the Ca2+-regulated mitochondrial aspartate–glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Dev Brain Res 143:33–46CrossRefGoogle Scholar
  35. 35.
    Cheeseman AJ, Clark JB (1988) Influence of the malate–aspartate shuttle on oxidative metabolism in synaptosomes. J Neurochem 50:1559–1565PubMedCrossRefGoogle Scholar
  36. 36.
    McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S (1993) Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 15:320–329PubMedCrossRefGoogle Scholar
  37. 37.
    Jalil MA, Begum L, Contreras L, Pardo B, Iijima M, Li MX, Ramos M, Marmol P, Horiuchi M, Shimotsu K, Nakagawa S, Okubo A, Sameshima M, Isashiki Y, del Arco A, Kobayashi K, Satrùstegui J, Saheki T (2005) Reduced N-acetylaspartate levels in mice lacking aralar, a brain and muscle-type mitochondrial aspartate–glutamate carrier. J Biol Chem 280:31333–31339PubMedCrossRefGoogle Scholar
  38. 38.
    D’Adamo AF Jr, Yatsu FM (1966) Acetate metabolism in the nervous system. N-acetyl-L-aspartic acid and the biosynthesis of brain lipids. J Neurochem 13:961–965PubMedCrossRefGoogle Scholar
  39. 39.
    Burri R, Steffen C, Herschkowitz N (1991) N-acetyl-aspartate is a major source of acetyl groups for lipid synthesis during rat brain development. Dev Neurosci 13:403–411PubMedCrossRefGoogle Scholar
  40. 40.
    Mehta V, Namboodiri MA (1995) N-acetylaspartate as an acetyl source in the nervous system. Brain Res Mol Brain Res 31:151–157PubMedCrossRefGoogle Scholar
  41. 41.
    Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW (2001) Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78:736–745PubMedCrossRefGoogle Scholar
  42. 42.
    Wibom R, Lasorsa F, Töhönen V, Barbaro M, Sterky F, Kucinski T, Naess K, Jonsson M, Pierri C, Palmieri F, Wedell A (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 361:489–495PubMedCrossRefGoogle Scholar
  43. 43.
    Heineman FW, Balaban RS (1990) Phosphorus-31 nuclear magnetic resonance analysis of transient changes of canine myocardial metabolism in vivo. J Clin Invest 85:843–852PubMedCrossRefGoogle Scholar
  44. 44.
    Sharma N, Okere IC, Brunengraber DZ, McElfresh TA, King KL, Sterk JP, Huang H, Chandler MP, Stanley WC (2005) Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation. J Physiol 562:593–603PubMedCrossRefGoogle Scholar
  45. 45.
    Hansford RG, Zorov D (1998) Role of mitochondrial calcium transport in the control of substrate oxidation. Mol Cell Biochem 184:359–369PubMedCrossRefGoogle Scholar
  46. 46.
    Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase. Am J Physiol Cell Physiol 278:423–435Google Scholar
  47. 47.
    Korzeniewski B (2007) Regulation of oxidative phosphorylation through parallel activation. Biophys Chem 129:93–110PubMedCrossRefGoogle Scholar
  48. 48.
    Rutter GA, Denton RM (1988) Regulation of NAD+-linked isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase by Ca2+ ions within toluene-permeabilized rat heart mitochondria. Interactions with regulation by adenine nucleotides and NADH/NAD+ ratios. Biochem J 252:181–189PubMedGoogle Scholar
  49. 49.
    Rutter GA, Midgley PJ, Denton RM (1989) Regulation of the pyruvate dehydrogenase complex by Ca2+ within toluene-permeabilized heart mitochondria. Biochim Biophys Acta 1014:263–270PubMedCrossRefGoogle Scholar
  50. 50.
    Das AM (2003) Regulation of the mitochondrial ATP-synthase in health and disease. Mol Genet Metab 79:71–82PubMedCrossRefGoogle Scholar
  51. 51.
    Gellerich FN, Gizatullina Z, Nguyen HP, Trumbeckaite S, Vielhaber S, Seppet E, Zierz S, Landwehrmeyer B, Ries O, von Hoersten S, Striggow F (2008) Impaired regulation of brain mitochondria by extramitochondrial Ca2+ in transgenic Huntington disease rats. J Biol Chem 283:30715–30724PubMedCrossRefGoogle Scholar
  52. 52.
    Gellerich FN, Gizatullina Z, Arandacikaite O, Jerzembeck D, Vielhaber S, Seppet E, Striggow F (2009) Extramitochondrial Ca2+ in the nanomolar range regulates glutamate-dependent oxidative phosphorylation on demand. PloS One 4:e8181PubMedCrossRefGoogle Scholar
  53. 53.
    Contreras L, Gomez-Puertas P, Iijima M, Kobayashi K, Saheki T, Satrústegui J (2007) Ca2+ activation kinetics of the two aspartate–glutamate mitochondrial carriers, aralar and citrin: role in the heart malate–aspartate NADH shuttle. J Biol Chem 282:7098–7106PubMedCrossRefGoogle Scholar
  54. 54.
    LaNoue KF, Meijer AJ, Brouwe A (1974) Evidence for electrogenic aspartate transport in rat liver mitochondria. Arch Biochem Biophys 161:544–550PubMedCrossRefGoogle Scholar
  55. 55.
    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (2004) Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31PubMedCrossRefGoogle Scholar
  56. 56.
    Hope CI, Sharp DM, Hemara-Wahanui A, Sissingh JI, Lundon P, Mitchell EA, Maw MA, Clover GM (2005) Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. Clin Experiment Ophthalmol 33:129–136PubMedCrossRefGoogle Scholar
  57. 57.
    Laumonnier F, Roger S, Guerin P, Molinari F, M’rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M, Romano V, Holbert S, Andres C, Chaabouni H, Colleaux L, Constant J, Le Guennec JY, Briault S (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 163:1622–1629PubMedCrossRefGoogle Scholar
  58. 58.
    Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM (2010) Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry 15:38–52PubMedCrossRefGoogle Scholar
  59. 59.
    Lepagnol-Bestel A, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide A, Moalic J, Muller D, Dean B, Yoshikawa T, Gorwood P, Buxbaum J, Ramoz N, Simonneau M (2008) SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry 13:385–397PubMedCrossRefGoogle Scholar
  60. 60.
    Sakurai T, Ramoz N, Barreto M, Gazdoiu M, Takahashi N, Gertner M, Dorr N, Sosa M, Gasperi R, Perez G, Schmeidler J, Mitropoulou V, Le H, Lupu M, Hof P, Elder G, Buxbaum J (2010) Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. Biol Psychiatry 67:887–894PubMedCrossRefGoogle Scholar
  61. 61.
    Zilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N (2006) Autism, the superior temporal sulcus and social perception. Trends Neurosci 29:359–366PubMedCrossRefGoogle Scholar
  62. 62.
    Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161:662–669PubMedCrossRefGoogle Scholar
  63. 63.
    Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L (2005) Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry 162:2182–2184PubMedCrossRefGoogle Scholar
  64. 64.
    Turunen JA, Rehnström K, Kilpinen H, Kuokkanen M, Kempas E, Ylisaukko-Oja T (2008) Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism. Autism Res 1:189–192PubMedCrossRefGoogle Scholar
  65. 65.
    Ramoz N, Cai G, Reichert JG, Silverman JM, Buxbaum JD (2008) An analysis of candidate autism loci on chromosome 2q24–q33: evidence for association to the STK39 gene. Am J Med Genet B Neuropsychiatr Genet 147:1152–1158Google Scholar
  66. 66.
    Silverman JM, Buxbaum JD, Ramoz N, Schmeidler J, Reichenberg A, Hollander E, Angelo G, Smith CJ, Kryzak LA (2008) Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism. Am J Med Genet B Neuropsychiatr Genet 147:408–410PubMedGoogle Scholar
  67. 67.
    Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E, International Molecular Genetic Study of Autism Consortium (IMGSAC) (2006) SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample. Eur J Hum Genet 14:123–126PubMedGoogle Scholar
  68. 68.
    Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA (2006) Lack of association between autism and SLC25A12. Am J Psychiatry 163:929–931PubMedCrossRefGoogle Scholar
  69. 69.
    Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM (2006) Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord 36:1137–1140PubMedCrossRefGoogle Scholar
  70. 70.
    Chien WH, Wu YY, Gau SS, Huang YS, Soong WT, Chiu YN, Chen CH (2010) Association study of the SLC25A12 gene and autism in Han Chinese in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry 34:189–192PubMedCrossRefGoogle Scholar
  71. 71.
    Pedersen P, Carafoli E (1987) Ion motive ATPases. I. Ubiquity, properties, and significance for cell function. Trends Biochem 14:146–150CrossRefGoogle Scholar
  72. 72.
    Chicka MC, Strehler EE (2003) Alternative splicing of the first intracellular loop of plasma membrane Ca2+-ATPase isoform 2 alters its membrane targeting. J Biol Chem 278:18464–18470PubMedCrossRefGoogle Scholar
  73. 73.
    Ficarella R, Di Leva F, Bortolozzi M, Ortolano S, Donaudy F, Petrillo M, Melchionda S, Lelli A, Domi T, Fedrizzi L, Lim D, Shull GE, Gasparini P, Brini M, Mammano F, Carafoli E (2007) A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness. Proc Natl Acad Sci USA 104:1516–1521PubMedCrossRefGoogle Scholar
  74. 74.
    Bortolozzi M, Brini M, Parkinson N, Crispino G, Scimemi P, De Siati RD, Di Leva F, Parker A, Ortolano S, Arslan E, Brown SD, Carafoli E, Mammano F (2010) The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice. J Biol Chem 285:37693–37703PubMedCrossRefGoogle Scholar
  75. 75.
    Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ (2005) Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med 352:1557–1564PubMedCrossRefGoogle Scholar
  76. 76.
    Rosenhall U, Nordin V, Brantberg K, Gillberg C (2003) Autism and auditory brain stem responses. Ear Hear 24:206–214PubMedCrossRefGoogle Scholar
  77. 77.
    Rosenhall U, Nordin V, Sandstrom M, Ahlsen G, Gillberg C (1999) Autism and hearing loss. J Autism Dev Disord 29:349–357PubMedCrossRefGoogle Scholar
  78. 78.
    Hu VW, Nguyen A, Kim KS, Steinberg ME, Sarachana T, Scully MA, Soldin SJ, Luu T, Lee NH (2009) Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis. PLoS One 4:e5775PubMedCrossRefGoogle Scholar
  79. 79.
    Carayol J, Sacco R, Tores F, Rousseau F, Lewin P, Hager J, Persico AM (2011) Converging evidence for an association of ATP2B2 allelic variants with autism in males. Biol Psychiatry (in press)Google Scholar
  80. 80.
    Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19:4072–4082PubMedCrossRefGoogle Scholar
  81. 81.
    Pessah IN, Cherednichenko G, Lein PJ (2010) Minding the calcium store: ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther 125:260–285PubMedCrossRefGoogle Scholar
  82. 82.
    Vallipuram J, Grenville J, Crawford DA (2010) The E646D-ATP13A4 mutation associated with autism reveals a defect in calcium regulation. Cell Mol Neurobiol 30:233–346PubMedCrossRefGoogle Scholar
  83. 83.
    Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281:22085–22091PubMedCrossRefGoogle Scholar
  84. 84.
    Piton A, Gauthier J, Hamdan FF, Lafrenière RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Côté M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Rivière JB, Tarabeux J, Cossette P, Krebs MO, Rapoport JL, Addington A, Delisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA (2010) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry. doi: 10.1038/mp.2010.54
  85. 85.
    Pavlowsky A, Gianfelice A, Pallotto M, Zanchi A, Vara H, Khelfaoui M, Valnegri P, Rezai X, Bassani S, Brambilla D, Kumpost J, Blahos J, Roux MJ, Humeau Y, Chelly J, Passafaro M, Giustetto M, Billuart P, Sala C (2010) A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr Biol 20:103–115PubMedCrossRefGoogle Scholar
  86. 86.
    Piton A, Michaud JL, Peng H, Aradhya S, Gauthier J, Mottron L, Champagne N, Lafrenière RG, Hamdan FF, S2D team, Joober R, Fombonne E, Marineau C, Cossette P, Dubé MP, Haghighi P, Drapeau P, Barker PA, Carbonetto S, Rouleau GA (2008) Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 17:3965–3974PubMedCrossRefGoogle Scholar
  87. 87.
    Handley MT, Lian LY, Haynes LP, Burgoyne RD (2010) Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder. PLoS One 5:e10534PubMedCrossRefGoogle Scholar
  88. 88.
    Sadakata T, Furuichi T (2009) Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility. Cerebellum 8:312–322PubMedCrossRefGoogle Scholar
  89. 89.
    Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, Ohkura T, Katoh-Semba R, Nakajima M, Sekine Y, Tanaka M, Nakamura K, Iwata Y, Tsuchiya KJ, Mori N, Detera-Wadleigh SD, Ichikawa H, Itohara S, Yoshikawa T, Furuichi T (2007) Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest 117:931–943PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Laboratory of Molecular Psychiatry & NeurogeneticsUniversity “Campus Bio-Medico”RomeItaly
  2. 2.Department of Experimental NeurosciencesI.R.C.C.S. “Fondazione Santa Lucia”RomeItaly
  3. 3.Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular BiologyUniversity of BariBariItaly
  4. 4.Consiglio Nazionale delle RicercheInstitute of Biomembranes and BioenergeticsBariItaly

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