Journal Mobile Options
Table of Contents
Vol. 54, No. 1, 2006
Issue release date: November 2006

Constitutional Downregulation of SEMA5A Expression in Autism

Melin M. · Carlsson B. · Anckarsater H. · Rastam M. · Betancur C. · Isaksson A. · Gillberg C. · Dahl N.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

There is strong evidence for the importance of genetic factors in idiopathic autism. The results from independent twin and family studies suggest that the disorder is caused by the action of several genes, possibly acting epistatically. We have used cDNA microarray technology for the identification of constitutional changes in the gene expression profile associated with idiopathic autism. Samples were obtained and analyzed from 6 affected subjects belonging to multiplex autism families and from 6 healthy controls. We assessed the expression levels for approximately 7,700 genes by cDNA microarrays using mRNA derived from Epstein-Barr virus-transformed B lymphocytes. The microarray data were analyzed in order to identify up- or downregulation of specific genes. A common pattern with nine downregulated genes was identified among samples derived from individuals with autism when compared to controls. Four of these nine genes encode proteins involved in biological processes associated with brain function or the immune system, and are consequently considered as candidates for genes associated with autism. Quantitative real-time PCR confirms the downregulation of the gene encoding SEMA5A, a protein involved in axonal guidance. Epstein-Barr virus should be considered as a possible source for altered expression, but our consistent results make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Fombonne E: Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord 2003;33:365–382.
  2. Kanner L: Autistic disturbances of affective contact. Nervous Child 1943;2:217–250.
  3. Folstein S, Rutter M: Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 1977;18:297–321.
  4. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M: A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989;30:405–416.
  5. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M: Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25:63–77.
  6. Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M: Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet 1995;57:717–726.
  7. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M: Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 1999;8:805–812.
  8. International Molecular Genetic Study of Autism Consortium: A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998;7:571–578.
  9. International Molecular Genetic Study of Autism Consortium: A genome wide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001;69:570–581.
  10. Collaborative Linkage Study of Autism: An autosomal genomic screen for autism. Am J Med Genet 2001;105:609–615.
  11. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers R, et al: A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999;65:493–507.
  12. Gillberg C: Chromosomal disorders and autism. J Autism Dev Disord 1998;28:415–425.
  13. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T: Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003;34:27–29.
  14. Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S: 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 2004;74:552–557.
  15. Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994;24:659–685.
  16. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Press, 1994.
  17. Ihaka R, Gentleman R: A language for data analysis and graphics. J Comput Graph Stat 1996;5:299–315.

    External Resources

  18. Goss Tuscher V, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci 2001;98:5116–5121.
  19. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J: Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 2001;57:1618–1628.
  20. Nolan PM, Peters J, Strivens M, Rogers D, Hagan J, Spurr N, Gray IC, Vizor L, Brooker D, Whitehill E, Washbourne R, Hough T, Greenaway S, Hewitt M, Liu X, McCormack S, Pickford K, Selley R, Wells C, Tymowska-Lalanne Z, Roby P, Glenister P, Thornton C, Thaung C, Stevenson JA, Arkell R, Mburu P, Hardisty R, Kiernan A, Erven A, Steel KP, Voegeling S, Guenet JL, Nickols C, Sadri R, Nasse M, Isaacs A, Davies K, Browne M, Fisher EM, Martin J, Rastan S, Brown SD, Hunter J: A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet 2000;25:440–443.
  21. Adams RH, Betz H, Puschel AW: A novel class of murine semaphorins with homology to thrombospondin is differentially expressed during early embryogenesis. Mech Dev 1996;57:33–45.
  22. Skaliora I, Singer W, Betz H, Puschel AW: Differential patterns of semaphorin expression in the developing rat brain. Eur J Neurosci 1998;10:1215–1229.
  23. Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL: Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 2004;44:961–975.
  24. Oster SF, Bodeker MO, He FSretavan DW: Invariant Sema5A inhibition serves an ensheathing function during optic nerve development. Development 2003;130:775–784.
  25. Jones L, Lopez-Bendito G, Gruss P, Stoykova A, Molnar Z: Pax6 is required for the normal development of the forebrain axonal connections. Development 2002;129:5041–5052.
  26. Simmons AD, Puschel AW, McPherson JD, Overhauser J, Lovett M: Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval. Biochem Biophys Res Commun 1998;242:685–691.
  27. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK: HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000;6:435–442.
  28. Millar DG, Garza KM, Odermatt B, Elford AR, Ono N, Li Z, Ohashi PS: Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 2003;9:1469–1476.
  29. Mycko MP, Cwiklinska H, Szymanski J, Szymanska B, Kudla G, Kilianek L, Odyniec A, Brosnan CF, Selmaj KW: Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II. J Immunol 2004;172:202–213.
  30. Bernal JNunez J: Thyroid hormones and brain development. Eur J Endocrinol 1995;133:390–398.
  31. Poguet AL, Legrand C, Feng X, Yen PM, Meltzer P, Samarut J, Flamant F: Microarray analysis of knockout mice identifies cyclin D2 as a possible mediator for the action of thyroid hormone during the postnatal development of the cerebellum. Dev Biol 2003;254:188–199.
  32. Huard JM, Forster CC, Carter ML, Sicinski P, Ross ME: Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 1999;126:1927–1935.
  33. Ingi T, Worley PF, Lanahan AA: Regulation of SSAT expression by synaptic activity. Eur J Neurosci 2001;13:1459–1463.
  34. Kaasinen SK, Oksman M, Alhonen L, Tanila H, Janne J: Spermidine/spermine N1-acetyltransferase overexpression in mice induces hypoactivity and spatial learning impairment. Pharmacol Biochem Behav 2004;78:35–45.
  35. Vincent JB, Herbrick JA, Gurling HM, Bolton PF, Roberts W, Scherer SW: Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am J Hum Genet 2000;67:510–514.
  36. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC: Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001;105:406–413.
  37. Cheung J, Petek E, Nakabayashi K, Tsui LC, Vincent JB, Scherer SW: Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31. Genomics 2001;78:7–11.
  38. Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, Wassink TH, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Marino R, Quattrocchi CC, Baldi A, Zelante L, Gasparini P, Keller F: Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 2001;6:150–159.
  39. Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr., Fang Y, Song CY, Vitale R: Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002;7:311–316.
  40. Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E: Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. Am J Hum Genet 1998;62:1077–1083.
  41. Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM, Ravan SA, Elston L, Decena K, Donnelly SL, Abramson RK, Wright HH, DeLong GR, Gilbert JR, Pericak-Vance MA: Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet 2003;72:539–548.
  42. Schopler E, Reichler RJ, Renner BR: The Childhood Autism Rating Scale (CARS) for Diagnostic Screening and Classification of Autism. New York, Irvington, 1986.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50