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Epigenetic Factors and Autism Spectrum Disorders

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Abstract

Autism is a complex neurodevelopmental disorder that has significant phenotypic overlap with several diseases, many of which fall within the broader category of autism spectrum disorders (ASDs). The etiology of the disorder is unclear and seems to involve a complex interplay of polygenic as well as environmental factors. We discuss evidence that suggests that epigenetic dysregulation is highly implicated as a contributing cause of ASDs and autism. Specifically, we examine neurodevelopmental disorders that share significant phenotypic overlap with ASDs and feature the dysregulation of epigenetically modified genes including UBE3A, GABA receptor genes, and RELN. We then look at the dysregulated expression of implicated epigenetic modifiers, namely MeCP2, that yield complex and varied downstream pleiotropic effects. Finally, we examine epigenetically mediated parent-of-origin effects through which paternal gene expression dominates that of maternal contributing to contrasting phenotypes implicated in ASDs. Such preliminary evidence suggests that elucidating the complex role of epigenetic regulations involved in ASDs could prove vital in furthering our understanding of the complex etiology of autism and ASDs.

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Abbreviations

3′UTR:

3′-Untranslated region

AG:

Androgenetic embryo, that is, one having two paternal genome copies

AS:

Angelman syndrome

ASDs:

Autism spectrum disorders

GABA:

Gamma-aminobutyric acid

HMGN1:

High mobility group N1 protein

PG:

Parthenogenetic, that is, one having two maternal genome copies

PWS:

Prader–Willi syndrome

RTT:

Rett syndrome

SSADH:

Succinic semialdehyde dehydrogenase deficiency

TRD:

Transcriptional repression domain

BDNF:

Brain-derived neurotrophic factor

DLX5 :

Encodes a member of a homeobox transcription factor gene family

EGR2:

Early growth response protein-2

GABRA5:

Gamma-aminobutyric acid (GABA) A receptor subunit, alpha 5

GABRB3:

Gamma-aminobutyric acid (GABA) A receptor subunit, beta 3

GABRG3:

Gamma-aminobutyric acid (GABA) A receptor, gamma 3

HMGN1:

Nonhistone chromosomal protein HMG-14

MeCP2:

Methyl CpG binding protein-2

RELN :

Encodes Reelin, important for neuronal migration

UBE3A :

Encodes ubiquitin-protein ligase E3A or E6AP ubiquitin-protein ligase (E6AP)

References

  • Abrahams, B. S., & Geschwind, D. H. (2008). Advances in autism genetics: On the threshold of a new neurobiology. Nature Reviews Genetics, 9, 341–355.

    PubMed  CAS  Google Scholar 

  • Abuhatzira, L., Shamir, A., Schones, D., Schaffer, A., & Bustin, M. (2011). The chromatin-binding protein HMGN1 regulates the expression of Methyl CpG-binding protein 2 (MECP2) and affects the behavior of mice. Journal of Biological Chemistry, 286(48), 42051–42062.

    PubMed  CAS  Google Scholar 

  • 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. Nature Genetics, 17, 75–78.

    PubMed  CAS  Google Scholar 

  • Amir, R., Van den Veyver, I., Wan, M., Tran, C., & Zoghbi, H. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23(2), 185–188.

    PubMed  CAS  Google Scholar 

  • Badcock, C., & Crespi, B. (2006). Imbalanced genomic imprinting in brain development: An evolutionary basis for the aetiology of autism. Journal of Evolutionary Biology, 19, 1007–1032.

    PubMed  CAS  Google Scholar 

  • Baron-Cohen, S. (2002). The extreme male brain theory of autism. Trends in Cognitive Sciences, 6, 248–254. doi:10.1016/S1364-6613(02)01904-6.

    PubMed  Google Scholar 

  • Baron-Cohen, S., & Belmonte, M. K. (2005). Autism: A window onto the development of the social and the analytic brain. Annual Review of Neuroscience, 28, 109–126.

    PubMed  CAS  Google Scholar 

  • Basan, A., & Leucht, S. (2004). Valproate for schizophrenia. Cochrane Database of Systematic Reviews:004028. doi:10.1002/14651858.CD004028.pub2.

  • Belmonte, M. K., Cook, E. H, Jr, Anderson, G. M., Rubenstein, J. L., Greenough, W. T., Beckel-Mitchener, A., et al. (2004). Autism as a disorder of neural information processing: Directions for research and targets for therapy. Molecular Psychiatry, 9, 646–663.

    PubMed  CAS  Google Scholar 

  • Bertoglio, K., & Hendren, R. L. (2009). New developments in autism. Psychiatric Clinics of North America, 32, 1–14.

    PubMed  Google Scholar 

  • Bishop, D. V., Canning, E., Elgar, K., Morris, E., Jacobs, P. A., & Skuse, D. H. (2000). Distinctive patterns of memory function in subgroups of females with Turner syndrome: Evidence for imprinted loci on the X-chromosome affecting neurodevelopment. Neuropsychologia., 38, 712–721.

    PubMed  CAS  Google Scholar 

  • Bolton, P. F., Dennis, N. R., Browne, C. E., Thomas, N. S., Veltman, M. W., Thompson, R. J., et al. (2001). The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. American Journal of Medical Genetics, 105, 675–685.

    PubMed  CAS  Google Scholar 

  • Bromer, J. G., Wu, J., Zhou, Y., & Taylor, H. S. (2009). Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: An epigenetic mechanism for altered developmental programming. Endocrinology, 150, 3376–3382. doi:10.1210/en.2009-0071.

    PubMed  CAS  Google Scholar 

  • Burt, A., & Trivers, R. (1998). Genetic conflicts in genomic imprinting. Proceedings of the Royal Society of London. Series B: Biological Sciences, 265, 2393–2397.

    PubMed  CAS  Google Scholar 

  • Chahrour, M., & Zoghbi, H. (2007). The story of Rett syndrome: From clinic to neurobiology. Neuron, 56(3), 422–437.

    PubMed  CAS  Google Scholar 

  • Chelly, J. M. K., Francis, F., Cherif, B., & Bienvenu, T. (2006). Genetics and pathophysiology of mental retardation. European Journal of Human Genetics, 14, 701–713.

    PubMed  CAS  Google Scholar 

  • Childs, J. A., & Blair, J. L. (1997). Valproic acid treatment of epilepsy in autistic twins. Journal of Neuroscience Nursing, 29, 244–248.

    PubMed  CAS  Google Scholar 

  • Cohen, D., Pichard, N., Tordjman, S., Baumann, C., Burglen, L., Excoffier, E., et al. (2005). Specific genetic disorders and autism: Clinical contribution towards their identification. Journal of Autism and Developmental Disorders, 35(1), 103–116.

    PubMed  Google Scholar 

  • Cook, E. H, Jr, Courchesne, R. Y., Cox, N. J., Lord, C., Gonen, D., Guter, S. J., et al. (1998). Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. American Journal of Human Genetics, 62, 1077–1083.

    PubMed  CAS  Google Scholar 

  • Crespi, B. (2008). Genomic imprinting in the development and evolution of psychotic spectrum conditions. Biological Reviews, 83, 441–493. doi:10.1111/j.1469-185X.2008.00050.x.

    PubMed  Google Scholar 

  • Crespi, B., & Badcock, C. (2008). Psychosis and autism as diametrical disorders of the social brain. Behavioral & Brain Sciences., 31, 241–261.

    Google Scholar 

  • Creswell, C. S., & Skuse, D. H. (1999). Autism in association with Turner syndrome: Genetic implications for male vulnerability to pervasive developmental disorders. Neurocase., 5, 101–108.

    Google Scholar 

  • Currenti, S. (2010). Understanding and determining the etiology of autism. Cellular and Molecular Neurobiology, 30, 161–171.

    PubMed  Google Scholar 

  • Davies, W., Isles, A. R., Humby, T., & Wilkinson, L. S. (2008). What are imprinted genes doing in the brain? Advances in Experimental Medicine and Biology, 626, 62–70.

    PubMed  CAS  Google Scholar 

  • Davies, W., Isles, A. R., & Wilkinson, L. S. (2001). Imprinted genes and mental dysfunction. Annals of Medicine, 33, 428–436.

    PubMed  CAS  Google Scholar 

  • Davies, W., Isles, A. R., & Wilkinson, L. S. (2005). Imprinted gene expression in the brain. Neuroscience and Biobehavioral Reviews, 29, 421–430. doi:10.1016/j.neubiorev.2004.11.007.

    PubMed  CAS  Google Scholar 

  • Day, T., & Bonduriansky, R. (2004). Intralocus sexual conflict can drive the evolution of genomic imprinting. Genetics, 167, 1537–1546.

    PubMed  Google Scholar 

  • de la Casa-Esperon, E., & Sapienza, C. (2003). Natural selection and the evolution of genome imprinting. Annual Review of Genetics, 37, 349–370.

    PubMed  Google Scholar 

  • Donnelly, S. L., Wolpert, C. M., Menold, M. M., Bass, M. P., Gilbert, J. R., Cuccaro, M. L., et al. (2000). Female with autistic disorder and monosomy X (Turner syndrome): Parent-of-origin effect of the X chromosome. American Journal of Medical Genetics, 96, 312–316.

    PubMed  CAS  Google Scholar 

  • Driscoll, D. J., Waters, M. F., Williams, C. A., Zori, R. T., Glenn, C. C., Avidano, K. M., et al. (1992). A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics, 13, 917–924.

    PubMed  CAS  Google Scholar 

  • Dutta, S., Guhathakurta, S., Sinha, S., Chatterjee, A., Ahmed, S., Ghosh, S., et al. (2007). Reelin gene polymorphisms in the Indian population: a possible paternal 5′UTR-CGG-repeat-allele effect on autism. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, 144B, 106–112.

    CAS  Google Scholar 

  • Dykens, E. M., Sutcliffe, J. S., & Levitt, P. (2004). Autism and 15q11-q13 disorders: Behavioral, genetic, and pathophysiological issues. Mental Retardation & Developmental Disabilities Research Reviews., 10, 284–291.

    Google Scholar 

  • Fatemi, S. H., Snow, A. V., Stary, J. M., Araghi-Niknam, M., Reutiman, T. J., Lee, S., et al. (2005). Reelin signaling is impaired in autism. Biological Psychiatry, 57, 777–787.

    PubMed  CAS  Google Scholar 

  • Fradin, D., Cheslack-Postava, K., Ladd-Acosta, C., Newschaffer, C., Chakravarti, A., Arking, D. E., et al. (2010). Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs. PLoS ONE [Electronic Resource], 5(9).

  • Frank, S. A., & Crespi, B. J. (2011). Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over sexually antagonistic traits. Proceedings of the National Academy of Sciences of the United States of America, 108, 10886–10893.

    PubMed  CAS  Google Scholar 

  • Geschwind, D. H., & Levitt, P. (2007). Autism spectrum disorders: Developmental disconnection syndromes. Current Opinion in Neurobiology, 17, 103–111.

    PubMed  CAS  Google Scholar 

  • Gonzales, M., & LaSalle, J. (2010). The role of MeCP2 in brain development and neurodevelopmental disorders. Current Psychiatry Reports, 12, 127–134.

    PubMed  Google Scholar 

  • Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions. American Journal of Psychiatry, 160, 636–645.

    PubMed  Google Scholar 

  • Graff, J., & Mansuy, I. (2009). Epigenetic dysregulation in cognitive disorders. European Journal of Neuroscience, 30(1), 1–8.

    PubMed  Google Scholar 

  • Grafodatskaya, D., Chung, B., Szatmari, P., & Weksberg, R. (2010). Autism spectrum disorders and epigenetics. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 794–809.

    PubMed  Google Scholar 

  • Gregory, P. D., Schmid, A., Zavari, M., Lui, L., Berger, S. L., & Horz, W. (1998). Absence of Gcn5 HAT activity defines a novel state in the opening of chromatin at the PHO5 promoter in yeast. Molecular Cell, 1, 495–505.

    PubMed  CAS  Google Scholar 

  • Haig, D. (2000a). Genomic imprinting, sex-biased dispersal, and social behavior. Annals of the New York Academy of Sciences, 907, 149–163. doi:10.1111/j.1749-6632.2000.tb06621.x.

    PubMed  CAS  Google Scholar 

  • Haig, D. (2000b). The kinship theory of genomic imprinting. Annual Review of Ecology and Systematics, 31, 9–32.

    Google Scholar 

  • Haig, D. (2004). Genomic imprinting and kinship: How good is the evidence? Annual Review Genetics, 38, 553–585.

    CAS  Google Scholar 

  • Haig, D. (2006). Intragenomic politics. Cytogenetic & Genome Research., 113, 68–74.

    CAS  Google Scholar 

  • Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., et al. (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Archives of General Psychiatry, 68, 1095–1102.

    PubMed  Google Scholar 

  • Hammar, S., Dorrani, N., Dragich, J., Kudo, S., & Schanen, C. (2002). The phenotypic consequences of MECP2 mutations extend beyond Rett syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 8(2), 94–98.

    Google Scholar 

  • Hansen, J., Ghosh, R., & Woodcock, C. (2010). Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin. IUBMB Life, 62(10), 732–738.

    PubMed  CAS  Google Scholar 

  • Hogart, A., Martin, M., & Lasalle, J. (2006). Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with Aberrant MECP2 promoter methylation. Epigenetics., 1(4), 1–11.

    Google Scholar 

  • Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & Lasalle, J. M. (2007). 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics, 16, 691–703.

    PubMed  CAS  Google Scholar 

  • Hogart, A., Wu, D., LaSalle, J. M., & Schanen, N. C. (2010). The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiology of Diseases, 38, 181–191.

    CAS  Google Scholar 

  • Hollander, E., Soorya, L., Wasserman, S., Esposito, K., Chaplin, W., & Anagnostou, E. (2006). Divalproex sodium versus placebo in the treatment of repetitive behaviours in autism spectrum disorder. International Journal of Neuropsychopharmacology, 9, 209–213.

    PubMed  CAS  Google Scholar 

  • Horike, S., Shutao, C., Masaru, M., Jan-Fang, C., & Kohwi-Shigematsu, T. (2005). Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett Syndrome. Nature Genetics, 37, 31–40.

    PubMed  CAS  Google Scholar 

  • Jedele, K. B. (2007). The overlapping spectrum of Rett and Angelman syndromes: A clinical review. Seminars in Pediatric Neurology, 14, 108–117.

    PubMed  Google Scholar 

  • Jiang, Y. H., Sahoo, T., Michaelis, R. C., Bercovich, D., Bressler, J., Kashork, C. D., et al. (2004). A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. American Journal of Medical Genetics Part A., 131, 1–10.

    PubMed  Google Scholar 

  • Jones, P., Veenstra, G., Wage, P., Varmaak, D., Kass, S., Landsberger, N., et al. (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genetics, 19(2), 187–191.

    PubMed  CAS  Google Scholar 

  • Keverne, E. B. (1997). Genomic imprinting in the brain. Current Opinion in Neurobiology, 7, 463–468.

    PubMed  CAS  Google Scholar 

  • Keverne, E. B. (2001). Genomic imprinting and the maternal brain. Progress in Brain Research, 133, 279–285.

    PubMed  CAS  Google Scholar 

  • Keverne, E. B., Fundele, R., Narasimha, M., Barton, S. C., & Surani, M. A. (1996). Genomic imprinting and the differential roles of parental genomes in brain development. Developmental Brain Research, 92, 91–100. doi:10.1016/0165-3806(95)00209-X.

    PubMed  CAS  Google Scholar 

  • Lalande, M., & Calciano, M. A. (2007). Molecular epigenetics of Angelman syndrome. Cellular and Molecular Life Sciences, 64, 947–960.

    PubMed  CAS  Google Scholar 

  • Li, J., Nguyen, L., Gleason, C., Lotspeich, L., Spiker, D., Risch, N., et al. (2004). Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics., 126B, 51–57.

    Google Scholar 

  • Lintas, C., & Persico, A. M. (2010). Neocortical RELN promoter methylation increases significantly after puberty. NeuroReport, 21, 114–118.

    PubMed  CAS  Google Scholar 

  • Lo, W. S., Trievel, R. C., Rojas, J. R., Duggan, L., Hsu, J. Y., Allis, C. D., et al. (2000). Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Molecular Cell, 5, 917–926.

    PubMed  CAS  Google Scholar 

  • Luna, B., Minshew, N. J., Garver, K. E., Lazar, N. A., Thulborn, K. R., Eddy, W. F., et al. (2002). Neocortical system abnormalities in autism: An fMRI study of spatial working memory. Neurology., 59, 834–840.

    PubMed  CAS  Google Scholar 

  • Ma, D. Q., Whitehead, P. L., Menold, M. M., Martin, E. R., Ashley-Koch, A. E., Mei, H., et al. (2005). Identification of significant association and gene–gene interaction of GABA receptor subunit genes in autism. American Journal of Human Genetics, 77, 377–388.

    PubMed  CAS  Google Scholar 

  • Martin, C., Duvall, J., Simon, J., Arreaza, M., Wilkes, K., Alvarez-Retuerto, A., et al. (2007). Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics The Official Publication of the International Society of Psychiatric Genetics, 144B(7), 869–876.

    PubMed  CAS  Google Scholar 

  • Martin, E. R., Menold, M. M., Wolpert, C. M., Bass, M. P., Donnelly, S. L., Ravan, S. A., et al. (2000). Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. American Journal of Medical Genetics, 96, 43–48.

    PubMed  Google Scholar 

  • McAlonan, G. M., Cheung, V., Cheung, C., Suckling, J., Lam, G. Y., Tai, K. S., et al. (2005). Mapping the brain in autism. A voxel-based MRI study of volumetric differences and intercorrelations in autism. Brain., 128, 268–276.

    PubMed  Google Scholar 

  • McCauley, J. L., Olson, L. M., Delahanty, R., Amin, T., Nurmi, E. L., Organ, E. L., et al. (2004). A linkage disequilibrium map of the 1-Mb 15q12 GABAA receptor subunit cluster and association to autism. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics., 131B, 51–59. doi:10.1002/ajmg.b.30038.

    Google Scholar 

  • McGrath, J., & Solter, D. (1984). Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell, 37, 179–183.

    PubMed  CAS  Google Scholar 

  • Minshew, N. J., Luna, B., & Sweeney, J. A. (1999). Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism. Neurology., 52, 917–922.

    PubMed  CAS  Google Scholar 

  • Moretti, P., & Zoghbi, H. (2006). MeCP2 dysfunction in Rett syndrome and related disorders. Current Opinion in Genetics and Development, 16(3):276–281.

    Google Scholar 

  • Nagarajan, R., Hogart, A., Gwye, Y., Martin, M., & LaSalle, J. (2006). Reduced MeCp2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics., 1(4), e1–e11.

    PubMed  Google Scholar 

  • Nan, X., & Bird, A. (2001). The biological functions of the methyl-CpG-binding protein MeCP2 and its implication in Rett syndrome. Brain and Development, 23, 32–37.

    Google Scholar 

  • Nazeer, A., & Ghaziuddin, M. (2012). Autism spectrum disorders: clinical features and diagnosis. Pediatric Clinics of North America, 59, 19–25.

    PubMed  Google Scholar 

  • Nicholls, R. D. (2000). The impact of genomic imprinting for neurobehavioral and developmental disorders. The Journal of Clinical Investigation, 105, 413–418.

    PubMed  CAS  Google Scholar 

  • Nicholls, R. D., & Knepper, J. L. (2001). Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annual Review of Genomics and Human Genetics, 2, 153–175.

    PubMed  CAS  Google Scholar 

  • Nurmi, E. L., Bradford, Y., Chen, Y., Hall, J., Arnone, B., Gardiner, M. B., et al. (2001). Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics, 77, 105–113.

    PubMed  CAS  Google Scholar 

  • Pearl, P. L., Novotny, E. J., Acosta, M. T., Jakobs, C., & Gibson, K. M. (2003). Succinic semialdehyde dehydrogenase deficiency in children and adults. Annals of Neurology, 54, S73–S80.

    PubMed  CAS  Google Scholar 

  • Persico, A. M., & Bourgeron, T. (2006). Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends in Neurosciences, 29, 349–358.

    PubMed  CAS  Google Scholar 

  • Persico, A. M., D’Agruma, L., Maiorano, N., Totaro, A., Militerni, R., Bravaccio, C., et al. (2001). Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Molecular Psychiatry, 6, 150–159.

    PubMed  CAS  Google Scholar 

  • Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., & Klein, P. S. (2001). Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. Journal of Biological Chemistry, 276, 36734–36741.

    PubMed  CAS  Google Scholar 

  • Ramocki, M., Tavyev, Y., & Peters, S. (2010). The MECP2 duplication syndrome. American Journal of Medical Genetics Part A, 152A(5), 1079–1088.

    PubMed  Google Scholar 

  • Riccio, A. (2010). Dynamic epigenetic regulation in neurons: Enzymes, stimuli and signaling pathways. Nature Neuroscience, 13(11), 1330–1337.

    PubMed  CAS  Google Scholar 

  • Rougeulle, C., Glatt, H., & Lalande, M. (1997). The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nature Genetics, 17, 14–15.

    PubMed  CAS  Google Scholar 

  • Sacco, R., Curatolo, P., Manzi, B., Militerni, R., Bravaccio, C., Frolli, A., et al. (2010). Principal pathogenetic components and biological endophenotypes in autism spectrum disorders. Autism Research Official Journal of the International Society for Autism Research, 3, 237–252.

    PubMed  Google Scholar 

  • Samaco, R. C., Hogart, A., & LaSalle, J. M. (2005). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483–492.

    PubMed  CAS  Google Scholar 

  • Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Human Molecular Genetics, 15, R138–R150.

    PubMed  CAS  Google Scholar 

  • Schmitz, C., van Kooten, I. A., Hof, P. R., van Engeland, H., Patterson, P. H., & Steinbusch, H. W. (2005). Autism: Neuropathology, alterations of the GABAergic system, and animal models. International Review of Neurobiology, 71, 1–26.

    PubMed  CAS  Google Scholar 

  • Schroer, R. J., Phelan, M. C., Michaelis, R. C., Crawford, E. C., Skinner, S. A., Cuccaro, M., et al. (1998). Autism and maternally derived aberrations of chromosome 15q. American Journal of Medical Genetics, 76, 327–336.

    PubMed  CAS  Google Scholar 

  • Schumann, C. M., Barnes, C. C., Lord, C., & Courchesne, E. (2009). Amygdala enlargement in toddlers with autism related to severity of social and communication impairments. Biological Psychiatry, 66, 942–949.

    PubMed  Google Scholar 

  • Schumann, C. M., Hamstra, J., Goodlin-Jones, B. L., Lotspeich, L. J., Kwon, H., Buonocore, M. H., et al. (2004). The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. Journal of Neuroscience, 24, 6392–6401.

    PubMed  CAS  Google Scholar 

  • Shibayama, A., Cook, E., Feng, J., Glanzmann, C., Yan, J., Craddock, N., et al. (2004). MECP2 structural and 3′-UTR variants in schizophrenia, autism and other psychiatric diseases: A possible association with autism. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics The Official Publication of the International Society of Psychiatric Genetics, 128B(1), 50–53.

    PubMed  Google Scholar 

  • Simonini, M. V., Camargo, L. M., Dong, E., Maloku, E., Veldic, M., Costa, E., et al. (2006). The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proceedings of the National Academy of Sciences of the United States of America, 103, 1587–1592.

    PubMed  CAS  Google Scholar 

  • Skaar, D. A., Shao, Y., Haines, J. L., Stenger, J. E., Jaworski, J., Martin, E. R., et al. (2005). Analysis of the RELN gene as a genetic risk factor for autism. Molecular Psychiatry, 10, 563–571.

    PubMed  CAS  Google Scholar 

  • Skuse, D. H. (2000). Imprinting, the X-chromosome, and the male brain: Explaining sex differences in the liability to autism. Pediatric Research, 47, 9–16.

    PubMed  CAS  Google Scholar 

  • Skuse, D. H., James, R. S., Bishop, D. V., Coppin, B., Dalton, P., Aamodt-Leeper, G., et al. (1997). Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature, 387, 705–708.

    PubMed  CAS  Google Scholar 

  • Steffenburg, S., Gillberg, C. L., Steffenburg, U., & Kyllerman, M. (1996). Autism in Angelman syndrome: A population-based study. Pediatric Neurology, 14, 131–136.

    PubMed  CAS  Google Scholar 

  • Surani, M. A., Barton, S. C., & Norris, M. L. (1984). Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature, 308, 548–550.

    PubMed  CAS  Google Scholar 

  • Swanberg, S., Nagarajan, R., Peddada, S., Yasui, D., & LaSalle, J. (2008). Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. Human Molecular Genetics, 18(3), 525–534.

    PubMed  Google Scholar 

  • Szyf, M. (2009). Epigenetics, DNA methylation, and chromatin modifying drugs. Annual Review of Pharmacology and Toxicology, 49, 243–263.

    PubMed  CAS  Google Scholar 

  • Takarae, Y., Minshew, N. J., Luna, B., & Sweeney, J. A. (2004). Oculomotor abnormalities parallel cerebellar histopathology in autism. Journal of Neurology, Neurosurgery and Psychiatry, 75, 1359–1361.

    CAS  Google Scholar 

  • Tremolizzo, L., Carboni, G., Ruzicka, W. B., Mitchell, C. P., Sugaya, I., Tueting, P., et al. (2002). An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proceedings of the National Academy of Sciences of the United States of America, 99, 17095–17100.

    PubMed  CAS  Google Scholar 

  • Urdinguio, R., Sanchez-Mut, J., & Esteller, M. (2009). Epigenetic mechanisms in neurological diseases: Genes, syndromes, and therapies. Lancet Neurology, 8(11), 1056–1072.

    PubMed  CAS  Google Scholar 

  • Veenstra-VanderWeele, J., & Cook, E. H, Jr. (2004). Molecular genetics of autism spectrum disorder. Molecular Psychiatry, 9, 819–832.

    PubMed  CAS  Google Scholar 

  • Veltman, M. W., Craig, E. E., & Bolton, P. F. (2005). Autism spectrum disorders in Prader-Willi and Angelman syndromes: A systematic review. Psychiatric Genetics, 15, 243–254.

    PubMed  Google Scholar 

  • Vermeulen, M., & Timmers, H. T. (2010). Grasping trimethylation of histone H3 at lysine 4. Epigenomics., 2, 395–406.

    PubMed  CAS  Google Scholar 

  • Viding, E., & Blakemore, S. J. (2007). Endophenotype approach to developmental psychopathology: Implications for autism research. Behavior Genetics, 37, 51–60.

    PubMed  Google Scholar 

  • Watanabe, M., Maemura, K., Kanbara, K., Tamayama, T., & Hayasaki, H. (2002). GABA and GABA receptors in the central nervous system and other organs. International Review of Cytology, 213, 1–47.

    PubMed  CAS  Google Scholar 

  • West, L., Waldrop, J., & Brunssen, S. (2009). Pharmacologic treatment for the core deficits and associated symptoms of autism in children. Journal of Pediatric Health Care., 23, 75–89.

    PubMed  Google Scholar 

  • Whittington, J., & Holland, A. (2010). Neurobehavioral phenotype in Prader-Willi syndrome. American Journal of Medical Genetics Part C, Seminars in Medical Genetics, 154C, 438–447.

    PubMed  Google Scholar 

  • Wilkinson, L. S., Davies, W., & Isles, A. R. (2007). Genomic imprinting effects on brain development and function. Nature Reviews Neuroscience, 8, 832–843.

    PubMed  CAS  Google Scholar 

  • Yasui, DS., Peddada, M., Bieda, R., Vallero, A., Hogart, R., Nagarajan, K., et al. (2007). Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. PNAS, 104, 19416–19421.

    Google Scholar 

  • Yisraeli, J. (1988). Effect of in vitro DNA methylation on beta-globin gene expression. Proceedings of the National Academy of Sciences of the United States of America, 85, 4638–4642.

    PubMed  CAS  Google Scholar 

  • Zahir, F. R., & Brown, C. J. (2011). Epigenetic impacts on neurodevelopment: Pathophysiological mechanisms and genetic modes of action. Pediatric Research, 69, 92R–100R. doi:10.1203/PDR.0b013e318213565e.

    PubMed  Google Scholar 

  • Zhang, H., Liu, X., Zhang, C., Mundo, E., Macciardi, F., Grayson, D. R., et al. (2002). Reelin gene alleles and susceptibility to autism spectrum disorders. Molecular Psychiatry, 7, 1012–1017.

    PubMed  CAS  Google Scholar 

  • Zhou, Z., Hong, E., Cohen, S., Zhao, W., Schmidt, L., Chen, W., et al. (2006). Brain-specific phosphorylation of MeCp2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron, 52(2), 255–269.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University School of Medicine, 3900 Reservoir Rd. NW, Washington, DC, 20057, USA

    Bess M. Flashner, Mark E. Russo, Jenine E. Boileau, Derek W. Leong & G. Ian Gallicano

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  1. Bess M. Flashner
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  2. Mark E. Russo
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  3. Jenine E. Boileau
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  4. Derek W. Leong
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  5. G. Ian Gallicano
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Correspondence to G. Ian Gallicano.

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Mark E. Russo, Bess M. Flashner, Jenine E. Boileau, Derek Leong: Contributed equally to this manuscript.

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Flashner, B.M., Russo, M.E., Boileau, J.E. et al. Epigenetic Factors and Autism Spectrum Disorders. Neuromol Med 15, 339–350 (2013). https://doi.org/10.1007/s12017-013-8222-5

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