Skip to main content

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

Fragile X syndrome and autism at the intersection of genetic and neural networks

Nature Neuroscience volume 9, pages 1221–1225 (2006)Cite this article

Abstract

Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Modifications of neuronal networks that increase susceptibility to autism spectrum conditions (ASC).

References

  1. Belmonte, M.K. et al. Autism and abnormal development of brain connectivity. J. Neurosci. 24, 9228–9231 (2004).

    Article  CAS  Google Scholar 

  2. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    Article  CAS  Google Scholar 

  3. Weiler, I.J. et al. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc. Natl. Acad. Sci. USA 94, 5395–5400 (1997).

    Article  CAS  Google Scholar 

  4. Hagerman, R.J. The physical and behavioral phenotype. in Fragile X Syndrome: Diagnosis, Treatment, and Research 3rd edn. (eds. Hagerman, R.J. & Hagerman, P.J.) 3–109 (Johns Hopkins Univ. Press, Baltimore, 2002).

    Google Scholar 

  5. Feinstein, C. & Reiss, A.L. Autism: the point of view from fragile X studies. J. Autism Dev. Disord. 28, 393–405 (1998).

    Article  CAS  Google Scholar 

  6. Sears, L.L. et al. An MRI study of the basal ganglia in autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 613–624 (1999).

    Article  CAS  Google Scholar 

  7. Hollander, E. et al. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol. Psychiatry 58, 226–232 (2005).

    Article  Google Scholar 

  8. Reiss, A.L., Abrams, M.T., Greenlaw, R., Freund, L. & Denckla, M.B. Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat. Med. 1, 159–167 (1995).

    Article  CAS  Google Scholar 

  9. Eliez, S., Blasey, C.M., Freund, L.S., Hastie, T. & Reiss, A.L. Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome. Brain 124, 1610–1618 (2001).

    Article  CAS  Google Scholar 

  10. Courchesne, E. et al. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging. AJR Am. J. Roentgenol. 162, 123–130 (1994).

    Article  CAS  Google Scholar 

  11. Kaufmann, W.E. et al. Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. J. Child Neurol. 18, 463–470 (2003).

    Article  Google Scholar 

  12. Fu, Y.H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

    Article  CAS  Google Scholar 

  13. Filipek, P.A. Medical aspects of autism. in Handbook of Autism and Pervasive Developmental Disorders 3rd edn. (eds. Volkmar, F.R., Paul, R., Klin, A. & Cohen, D.) 534–578 (Wiley, Hoboken, New Jersey, 2005).

    Google Scholar 

  14. Rogers, S.J., Wehner, D.E. & Hagerman, R.J. The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J. Dev. Behav. Pediatr. 22, 409–417 (2001).

    Article  CAS  Google Scholar 

  15. Clifford, S. et al. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J. Autism Dev. Disord. (in the press).

  16. Kaufmann, W.E. et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am. J. Med. Genet. A. 129, 225–234 (2004).

    Article  Google Scholar 

  17. Hagerman, R.J. Lessons from fragile X regarding neurobiology, autism, and neurodegeneration. J. Dev. Behav. Pediatr. 27, 63–74 (2006).

    Article  Google Scholar 

  18. Beckel-Mitchener, A. & Greenough, W.T. Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 10, 53–59 (2004).

    Article  Google Scholar 

  19. Bear, M.F., Huber, K.M. & Warren, S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).

    Article  CAS  Google Scholar 

  20. Pickett, J. & London, E. The neuropathology of autism: a review. J. Neuropathol. Exp. Neurol. 64, 925–935 (2005).

    Article  Google Scholar 

  21. Bauman, M.L. & Kemper, T.L. Neuroanatomic observations of the brain in autism: a review and future directions. Int. J. Dev. Neurosci. 23, 183–187 (2005).

    Article  Google Scholar 

  22. Casanova, M.F., Buxhoeveden, D.P., Switala, A.E. & Roy, E. Minicolumnar pathology in autism. Neurology 58, 428–432 (2002).

    Article  Google Scholar 

  23. Kogan, C.S. et al. Integrative cortical dysfunction and pervasive motion perception deficit in fragile X syndrome. Neurology 63, 1634–1639 (2004).

    Article  CAS  Google Scholar 

  24. Bertone, A., Mottron, L., Jelenic, P. & Faubert, J. Enhanced and diminished visuo-spatial information processing in autism depends on stimulus complexity. Brain 128, 2430–2441 (2005).

    Article  Google Scholar 

  25. Kogan, C.S. et al. Differential impact of the FMR1 gene on visual processing in fragile X syndrome. Brain 127, 591–601 (2004).

    Article  Google Scholar 

  26. Pellicano, E., Gibson, L., Maybery, M., Durkin, K. & Badcock, D.R. Abnormal global processing along the dorsal visual pathway in autism: a possible mechanism for weak visuospatial coherence? Neuropsychologia 43, 1044–1053 (2005).

    Article  Google Scholar 

  27. Johnson, M.H., Halit, H., Grice, S.J. & Karmiloff-Smith, A. Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis. Dev. Psychopathol. 14, 521–536 (2002).

    Article  Google Scholar 

  28. Kwiatkowski, D.J. & Manning, B.D. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. 14, R251–R258 (2005).

    Article  CAS  Google Scholar 

  29. Basu, T.N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).

    Article  CAS  Google Scholar 

  30. Costa, R.M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002).

    Article  CAS  Google Scholar 

  31. Butler, M.G. et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42, 318–321 (2005).

    Article  CAS  Google Scholar 

  32. Kwon, C.H. et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Zoghbi, H.Y. Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830 (2003).

    Article  CAS  Google Scholar 

  35. Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27–29 (2003).

    Article  CAS  Google Scholar 

  36. Laumonnier, F. et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am. J. Hum. Genet. 74, 552–557 (2004).

    Article  CAS  Google Scholar 

  37. Yan, J. et al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol. Psychiatry 10, 329–332 (2005).

    Article  CAS  Google Scholar 

  38. Vincent, J.B. et al. Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B, 82–84 (2004).

    Article  Google Scholar 

  39. Gauthier, J. et al. NLGN3/NLGN4 gene mutations are not responsible for autism in the Québec population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 132, 74–75 (2005).

    Article  Google Scholar 

  40. Ylisaukko-oja, T. et al. Analysis of four neuroligin genes as candidates for autism. Eur. J. Hum. Genet. 13, 1285–1292 (2005).

    Article  CAS  Google Scholar 

  41. Blasi, F. et al. Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141, 220–221 (2006).

    Article  Google Scholar 

  42. Comoletti, D. et al. The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J. Neurosci. 24, 4889–4893 (2004).

    Article  CAS  Google Scholar 

  43. Chih, B., Engelman, H. & Scheiffele, P. Control of excitatory and inhibitory synapse formation by neuroligins. Science 307, 1324–1328 (2005).

    Article  CAS  Google Scholar 

  44. Todd, P.K., Mack, K.J. & Malter, J.S. The fragile X mental retardation protein is required for type-1 metabotropic glutamate receptor-dependent translation of PSD-95. Proc. Natl. Acad. Sci. USA 100, 14374–14378 (2003).

    Article  CAS  Google Scholar 

  45. Rubenstein, J.L. & Merzenich, M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).

    Article  CAS  Google Scholar 

  46. Devlin, B. et al. Autism and the serotonin transporter: the long and short of it. Mol. Psychiatry 10, 1110–1116 (2005).

    Article  CAS  Google Scholar 

  47. Sutcliffe, J.S. et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am. J. Hum. Genet. 77, 265–279 (2005).

    Article  CAS  Google Scholar 

  48. Delorme, R. et al. Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder. Mol. Psychiatry 10, 1059–1061 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. Hollander, E., King, A., Delaney, K., Smith, C.J. & Silverman, J.M. Obsessive-compulsive behaviors in parents of multiplex autism families. Psychiatry Res. 117, 11–16 (2003).

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge all the people with autism spectrum conditions and their families who, by participating in our and others' studies, have generously contributed to the advancement of the autism field. T.B. is supported by Cure Autism Now, Fondation France Telecom, Fondation biomédicale de la mairie de Paris, AUMOLGEN FP6 and EUSynapse FP6.

Author information

Authors and Affiliations

  1. Department of Human Development, Cornell University, Martha Van Rensselaer Hall, Ithaca, 14853–4401, New York, USA

    Matthew K Belmonte

  2. Laboratoire de Génétique Humaine et Fonctions Cognitives, Institut Pasteur, 25 Rue du Docteur Roux, Paris, Cedex 15, 75015, France

    Thomas Bourgeron

  3. Université Paris 7, 2 Place Jussieu, Paris, Cedex 05, 75251, France

    Thomas Bourgeron

Authors
  1. Matthew K Belmonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Bourgeron
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Belmonte, M., Bourgeron, T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 9, 1221–1225 (2006). https://doi.org/10.1038/nn1765

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1765

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing