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Cell and Tissue Research

, Volume 371, Issue 1, pp 153–160 | Cite as

Autism spectrum disorders and disease modeling using stem cells

  • Anita Brito
  • Fabiele Baldino Russo
  • Alysson Renato Muotri
  • Patricia Cristina Baleeiro Beltrão-Braga
Review

Abstract

Autism spectrum disorders (ASD) represent a variety of disorders characterized as complex lifelong neurodevelopment disabilities, which may affect the ability of communication and socialization, including typical comportments like repetitive and stereotyped behavior. Other comorbidities are usually present, such as echolalia, hypotonia, intellectual disability and difficulties in processing figured speech. Furthermore, some ASD individuals may present certain abilities, such as eidetic memory, outstanding musical or painting talents and special mathematical skills, among others. Considering the variability of the clinical symptoms, one autistic individual can be severely affected in communication while others can speak perfectly, sometimes having a vocabulary above average in early childhood. The same variability can be seen in other clinical symptoms, thus the “spectrum” can vary from severe to mild. Induced pluripotent stem cell technology has been used to model several neurological diseases, including syndromic and non-syndromic autism. We discuss how modeling the central nervous system cells in a dish may help to reach a better understanding of ASD pathology and variability, as well as personalize their treatment.

Keywords

Autism spectrum disorders ASD iPSC Stem cells Disease modeling 

Notes

Acknowledgements

We would like to thank the support of the agency FAPESP (2011/20683-0, 09/51180-03), the NGO “the tooth fairy project, Brazil”, the National Institutes of Health (R01MH108528, R01MH094753, R01MH109885, R01MH100175, R56MH109587, U19MH107367), the “Autour des Williams” Association, a NARSAD Independent Investigator Grant (to A.R.M.) and to the ASD and control individuals and their families for donation of their teeth to “the tooth fairy project”.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. Acab A, Muotri AR (2015) The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment. Neurotherapeutics 12:534–545.  https://doi.org/10.1007/s13311-015-0354-x CrossRefPubMedPubMedCentralGoogle Scholar
  2. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188.  https://doi.org/10.1038/13810 CrossRefPubMedGoogle Scholar
  3. Bading H (2013) Nuclear calcium signalling in the regulation of brain function. Nat Rev Neurosci 14:593–608.  https://doi.org/10.1038/nrn3531 CrossRefPubMedGoogle Scholar
  4. Baudouin SJ (2013) Mouse models of autism: a common basis for syndromic and non syndromic autisms ? Med Sci 29:121–123.  https://doi.org/10.1051/medsci/2013292002 Google Scholar
  5. Boland MJ, Nazor KL, Tran HT, Szücs A, Lynch CL, Paredes R, Tassone F, Sanna PP, Hagerman RJ, Loring JF (2017) Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome. Brain 140:582–598.  https://doi.org/10.1093/brain/aww357 PubMedGoogle Scholar
  6. Callan MA, Zarnescu DC (2011) Heads-up: New roles for the fragile X mental retardation protein in neural stem and progenitor cells. Genesis 49:424–440.  https://doi.org/10.1002/dvg.20745 CrossRefPubMedGoogle Scholar
  7. Cassidy SB, Dykens E, Williams CA (2000) Prader-Willi and Angelman syndromes: Sister imprinted disorders. Am J Med Genet - Semin Med Genet 97:136–146.  https://doi.org/10.1002/1096-8628(200022)97:2%3C136::AID-AJMG5%3E3.0.CO;2-V
  8. Catterall WA, Leal K, Nanou E (2013) Calcium channels and short-term synaptic plasticity. J Biol Chem 288:10742–10749.  https://doi.org/10.1074/jbc.R112.411645 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cesaroni L, Garber M (1991) Exploring the experience of autism through firsthand accounts. J Autism Dev Disord 21:303–313.  https://doi.org/10.1007/BF02207327 CrossRefPubMedGoogle Scholar
  10. Chahrour M, Zoghbi HY (2007) The Story of Rett Syndrome: From Clinic to Neurobiology. Neuron 56:422–437.  https://doi.org/10.1016/j.neuron.2007.10.001 CrossRefPubMedGoogle Scholar
  11. Chailangkarn T, Trujillo CA, Freitas BC, Hrvoj-Mihic B, Herai RH, Yu DX, Brown TT, Marchetto MC, Bardy C, McHenry L, Stefanacci L, Järvinen A, Searcy YM, DeWitt M, Wong W, Lai P, Ard MC, Hanson KL, Romero S, Jacobs B, Dale AM, Dai L, Korenberg JR, Gage FHMA (2016) A human neurodevelopmental model for Williams syndrome. Nature 536:338–343.  https://doi.org/10.1038/nature19067 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chamberlain SJ, Chen P, Ng KY, Bourgois-Rocha F, Lemtiri-Chlieh F, Levine ES, Lalande M (2010) Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader – Willi syndromes. Proc Natl Acad Sci U S A 107:17668–17673.  https://doi.org/10.1073/pnas.1004487107/-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1004487107 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Christensen DL, Baio J, KVN B, Bilder D, Charles J, Constantino JN, Daniels J, Durkin MS, Fitzgerald RT, Kurzius-Spencer M, Lee LC, Pettygrove S, Robinson C, Schulz E, Wells C, Wingate MS, Zahorodny W, Yeargin-Allsopp M, Centers for Disease Control and Prevention (CDC) (2016) Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. Morb Mortal Wkly Rep 65:1–23Google Scholar
  14. Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandão WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltrão-Braga PCB (2016) The Brazilian Zika virus strain causes microcephaly. Nature 534:267–271.  https://doi.org/10.1038/nature18296 PubMedPubMedCentralGoogle Scholar
  15. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261.  https://doi.org/10.1016/j.cell.2011.06.013 CrossRefPubMedPubMedCentralGoogle Scholar
  16. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, AL MI, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD Study; Homozygosity Mapping Collaborative for Autism; UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–215.  https://doi.org/10.1038/nature13772 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, Zhang SC, Abbeduto L, Bhattacharyya A (2014) iPSC-Derived Forebrain Neurons from FXS Individuals Show Defects in Initial Neurite Outgrowth. Stem Cells Dev 23:1777–1787.  https://doi.org/10.1089/scd.2014.0030 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39:25–27CrossRefPubMedGoogle Scholar
  19. Ebert DHGM (2013) Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493:327–337.  https://doi.org/10.1038/jid.2014.371 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fink JJ, Robinson TM, Germain ND, Sirois CL, Bolduc KA, Ward AJ, Rigo F, Chamberlain SJ, Levine ES (2017) Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nat Commun 8:15038.  https://doi.org/10.1038/ncomms15038 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Germain ND, Chen P-F, Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, Bolduc KA, Robinson TM, Levine ES, Reiter LT, Graveley BR, Lalande M, Chamberlain SJ (2014) Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. Mol Autism 5:44.  https://doi.org/10.1186/2040-2392-5-44 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Geschwind DH (2011) Genetics of Autism Spectrum Disorders. Trends Cogn Sci 15:409–416.  https://doi.org/10.1016/j.tics.2011.07.003 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gomathi M, Balachandar V (2017) Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology. Stem Cell Investig 4:20.  10.21037/sci.2017.02.11 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X, Nunez Y, Walker MF, Murdoch JD, Sanders SJ, Fernandez TV, Ji W, Lifton RP, Vadasz E, Dietrich A, Pradhan D, Song H, Ming GL, Gu X, Haddad G, Marchetto MC, Spitzer N, Passos-Bueno MR, State MW, Muotri AR (2015) Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 20:1350–1365.  https://doi.org/10.1038/mp.2014.141 CrossRefPubMedGoogle Scholar
  25. Grzadzinski R, Huerta M, Lord C (2013) DSM-5 and autism spectrum disorders (ASDs): an opportunity for identifying ASD subtypes. Mol Autism 4:12.  https://doi.org/10.1186/2040-2392-4-12 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hagerman RHP (2013) Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol 12:786–798.  https://doi.org/10.1016/S1474-4422(13)70125-X CrossRefPubMedPubMedCentralGoogle Scholar
  27. Halevy T, Czech C, Benvenisty N (2015) Molecular mechanisms regulating the defects in fragile x syndrome neurons derived from human pluripotent stem cells. Stem Cell Rep 4:37–46.  https://doi.org/10.1016/j.stemcr.2014.10.015 CrossRefGoogle Scholar
  28. Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99:7746–7750.  https://doi.org/10.1073/pnas.122205699 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–221.  https://doi.org/10.1038/nature13908 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kaufmann M, Schuffenhauer A, Fruh I, Klein J, Thiemeyer A, Rigo P, Gomez-Mancilla B, Heidinger-Millot V, Bouwmeester T, Schopfer U, Mueller M, Fodor BD, Cobos-Correa A (2015) High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome. J Biomol Screen 20:1101–1111.  https://doi.org/10.1177/1087057115588287 CrossRefPubMedGoogle Scholar
  31. Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira LM, Finkelstein Y, Nelson CA 3rd, Vogel-Farley V, DeGregorio G, Holm IA, Khatwa U, Kapur K, Alexander ME, Finnegan DM, Cantwell NG, Walco AC, Rappaport L, Gregas M, Fichorova RN, Shannon MW, Sur M, Kaufmann WE (2014) Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A 111:4596–4601.  https://doi.org/10.1073/pnas.1311141111 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Knoll JHM, Nicholls RD, Magenis RE, Graham JM Jr, Lalande M, Latt SA (1989) Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet 32:285–290.  https://doi.org/10.1002/ajmg.1320320235 CrossRefPubMedGoogle Scholar
  33. Kolevzon A, Bush L, Wang A, Halpern D, Frank Y, Grodberg D, Rapaport R, Tavassoli T, Chaplin W, Soorya L, Buxbaum JD (2014) A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism 5:54.  https://doi.org/10.1186/2040-2392-5-54 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kover ST, McDuffie AS, Hagerman RJ, Abbeduto L (2013) Receptive Vocabulary in Boys with Autism Spectrum Disorder: Cross-Sectional Developmental Trajectories. J Autism Dev Disord 43:2696–2709.  https://doi.org/10.1038/jid.2014.371 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Krey JF, Pasca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, Dolmetsch RE (2013) Timothy Syndrome is associated with activity-dependent dendriticretraction in rodent and human neurons. Nat Neurosci 16:201–209.  https://doi.org/10.1038/nn.3307 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kumari D, Swaroop M, Southall N, Huang W, Zheng W, Usdin K (2015) High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells. Stem Cells Transl Med 4:800–808.  https://doi.org/10.5966/sctm.2014-0278 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Leonard H, Cobb S, Downs J (2016) Clinical and biological progress over 50 years in Rett syndrome. Nat Publ Gr 13:37–51.  https://doi.org/10.1038/nrneurol.2016.186 Google Scholar
  38. Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, Hutson A, Nicholls RD, Zori RT, Williams CA, Driscoll DJ (2001) Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 38:834–845.  https://doi.org/10.1136/jmg.38.12.834 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lu P, Chen X, Feng Y, Zeng Q, Jiang C, Zhu X, Fan G, Xue Z (2016) Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation. Sci China Life Sci 59:1093–1105.  https://doi.org/10.1007/s11427-016-0194-6 CrossRefPubMedGoogle Scholar
  40. Marchetto MCN, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR (2010) A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. Cell 143:527–539.  https://doi.org/10.1016/j.cell.2010.10.016 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC, Beltrao-Braga PC, Trujillo CA, Mendes AP, Padmanabhan K, Nunez Y, Ou J, Ghosh H, Wright R, Brennand KJ, Pierce K, Eichenfield L, Pramparo T, Eyler LT, Barnes CC, Courchesne E, Geschwind DH, Muotri AR (2016) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry.  https://doi.org/10.1016/j.pmr.2014.05.001
  42. Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M, Szekely A, Palejev D, Wilson M, Gerstein M, Grigorenko EL, Chawarska K, Pelphrey KA, Howe JR, Vaccarino FM (2015) FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell 162:375–390.  https://doi.org/10.1016/j.cell.2015.06.034 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Martins-Taylor K, Hsiao JS, Chen PF, Glatt-Deeley H, De Smith AJ, Blakemore AI, Lalande M, Chamberlain SJ (2014) Imprinted expression of UBE3A in non-neuronal cells from a Prader-willi syndrome patient with an atypical deletion. Hum Mol Genet 23:2364–2373.  https://doi.org/10.1093/hmg/ddt628 CrossRefPubMedGoogle Scholar
  44. McLennan Y, Polussa J, Tassone F, Hagerman R (2011) Fragile X Syndrome. Curr Genomics 12:216–224.  https://doi.org/10.2174/138920211795677886 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F (2015) Towards a therapy for Angelman syndrome by reduction of a long non-coding RNA. Nature 518:409–412.  https://doi.org/10.1038/nature13975 CrossRefPubMedGoogle Scholar
  46. Naisbitt S, Eunjoon K, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, Sheng M (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23:569–582.  https://doi.org/10.1016/S0896-6273(00)80809-0 CrossRefPubMedGoogle Scholar
  47. Nygren G, Cederlund M, Sandberg E, Gillstedt F, Arvidsson T, Carina Gillberg I, Westman Andersson G, Gillberg C (2012) The prevalence of autism spectrum disorders in toddlers: A population study of 2-year-old Swedish children. J Autism Dev Disord 42:1491–1497.  https://doi.org/10.1007/s10803-011-1391-x CrossRefPubMedGoogle Scholar
  48. Paşca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Paşca AM, Cord B, Palmer TD, Chikahisa S, Nishino S, Bernstein JA, Hallmayer J, Geschwind DHDR (2011) Using iPS cell-derived neurons to uncover cellular phenotypes associated with Timothy Syndrome. Nat Med 17:1657–1662.  https://doi.org/10.1038/nm.2576 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Phelan K, Mcdermid HE (2012) The 22q13. 3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndr 2:186–201.  https://doi.org/10.1159/000334260 Google Scholar
  50. Pierce K, Carter C, Weinfeld M, Desmond J, Hazin R, Bjork R, Gallagher N (2011) Detecting, Studying, and Treating Autism Early: The One-Year Well-Baby Check-Up Approach. J Pediatr 159:458–465.  https://doi.org/10.1016/j.jpeds.2011.02.036 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW (2014) Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders. Am J Hum Genet 94:677–694.  https://doi.org/10.1016/j.ajhg.2014.03.018 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Quaak I, Brouns MR, van de Bor M (2013) The dynamics of Autism Spectrum Disorders: How neurotoxic compounds and neurotransmitters interact. Int J Environ Res Public Health 10:3384–3408.  https://doi.org/10.3390/ijerph10083384 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Rougeulle C, Glatt HLM (1997) The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 17:14–15.  https://doi.org/10.1038/nm0798-822 CrossRefPubMedGoogle Scholar
  54. Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639.  https://doi.org/10.1093/hmg/ddh063 CrossRefPubMedGoogle Scholar
  55. Sarasua SM, Dwivedi A, Boccuto L, Chen CF, Sharp JL, Rollins JD, Collins JS, Rogers RC, Phelan K, DuPont BR (2014) 22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome. Genet Med 16:318–328.  https://doi.org/10.1038/gim.2013.144 CrossRefPubMedGoogle Scholar
  56. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:267–271.  https://doi.org/10.1038/nature12618 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, Loring JF, Haggarty SJ (2011) Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS ONE.  https://doi.org/10.1371/journal.pone.0026203
  58. 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) CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31.  https://doi.org/10.1016/j.cell.2004.09.011 CrossRefPubMedGoogle Scholar
  59. Stanurova J, Neureiter A, Hiber M, de Oliveira KH, Stolp K, Goetzke R, Klein D, Bankfalvi A, Klump H, Steenpass L (2016) Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing. Sci Rep 6:30792.  https://doi.org/10.1038/srep30792 CrossRefPubMedPubMedCentralGoogle Scholar
  60. State MWLP (2014) The Conundrums of Understanding Genetic Risks for Autism Spectrum Disorders. Nat Neurosci 14:1499–1506.  https://doi.org/10.1038/nn.2924 CrossRefGoogle Scholar
  61. Tian Y, Voineagu I, Paşca SP, Won H, Chandran V, Horvath S, Dolmetsch RE, Geschwind DH (2014) Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med 6:75.  https://doi.org/10.1186/s13073-014-0075-5 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Tonelli A, D’Angelo MG, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi AC, Bresolin N, Bassi MT (2006) Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. J Neurol Sci 241:13–17.  https://doi.org/10.1016/j.jns.2005.10.007 CrossRefPubMedGoogle Scholar
  63. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D (2002) Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci U S A 99:13284–13289.  https://doi.org/10.1073/pnas.192242399 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Urbach A, Bar-Nur O, Daley G, Benvenisty N (2010) Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6:407–411.  https://doi.org/10.1016/j.stem.2010.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Vicidomini C, Ponzoni L, Lim D, Schmeisser MJ, Reim D, Morello N, Orellana D, Tozzi A, Durante V, Scalmani P, Mantegazza M, Genazzani AA, Giustetto M, Sala M, Calabresi P, Boeckers TM, Sala C, Verpelli C (2017) Homer1b/c clustering is impaired in Phelan-McDermid Syndrome iPSCs derived neurons. Mol Psychiatry 22:637–637.  https://doi.org/10.1038/mp.2017.82 CrossRefPubMedGoogle Scholar
  66. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, WM MM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–533.  https://doi.org/10.1038/nature07999 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH (2011) Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet 20:3093–3108.  https://doi.org/10.1093/hmg/ddr212 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JAWJ (2006) Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 140:413–418.  https://doi.org/10.1002/ajmg.a CrossRefPubMedGoogle Scholar
  69. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, Ananiev GE, Mok JC, Lin BR, Lu J, Chiao C, Cherney R, Li H, Zhang SC, Chang Q (2014) Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wildtype neurons. Hum Mol Genet 23:2968–2980.  https://doi.org/10.1093/hmg/ddu008 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Wilson HL, Wong ACC, Shaw SR, Tse WY, Stapleton GA, Phelan MC, Hu S, Marshall J, McDermid HE (2003) Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet 40:575–584.  https://doi.org/10.1136/jmg.40.8.575 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Wing L, Gould J (1979) Severe impairment of social interactions and associated abnormalities in children: epidemiology and classification. J Autism Dev Disord 9:11–29.  https://doi.org/10.1007/BF01531288 CrossRefPubMedGoogle Scholar
  72. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE (2011) Using iPS cells to invetsigate cardiac phenotype in patients with Timothy Syndrome. Nature 471:230–234.  https://doi.org/10.1038/nature09855 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Anita Brito
    • 1
    • 2
  • Fabiele Baldino Russo
    • 1
    • 2
  • Alysson Renato Muotri
    • 3
  • Patricia Cristina Baleeiro Beltrão-Braga
    • 1
    • 2
    • 4
  1. 1.Department of Surgery, Stem Cell LaboratoryUniversity of São PauloSão PauloBrazil
  2. 2.Department of Microbiology, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
  3. 3.School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell ProgramUniversity of California San DiegoLa JollaUSA
  4. 4.Department of ObstetricsSchool of Arts Sciences and HumanitiesSão PauloBrazil

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