Constitutional Downregulation of SEMA5A Expression in Autism

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.

[1]  Michael J. Hansen,et al.  Semaphorin 5A Is a Bifunctional Axon Guidance Cue Regulated by Heparan and Chondroitin Sulfate Proteoglycans , 2004, Neuron.

[2]  H. Tanila,et al.  Spermidine/spermine N 1-acetyltransferase overexpression in mice induces hypoactivity and spatial learning impairment , 2004, Pharmacology Biochemistry and Behavior.

[3]  Albert David,et al.  X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. , 2004, American journal of human genetics.

[4]  Jacek Szymanski,et al.  Inducible Heat Shock Protein 70 Promotes Myelin Autoantigen Presentation by the HLA Class II1 , 2004, The Journal of Immunology.

[5]  P. Ohashi,et al.  Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo , 2003, Nature Medicine.

[6]  E. Fombonne.  Epidemiological Surveys of Autism and Other Pervasive Developmental Disorders: An Update , 2003, Journal of autism and developmental disorders.

[7]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[8]  M A Pericak-Vance,et al.  Fine mapping of autistic disorder to chromosome 15q11‐q13 by use of phenotypic subtypes. , 2003, American journal of human genetics.

[9]  D. Sretavan,et al.  Invariant Sema5A inhibition serves an ensheathing function during optic nerve development , 2003, Development.

[10]  P. Meltzer,et al.  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. , 2003, Developmental biology.

[11]  Z. Molnár,et al.  Pax6 is required for the normal development of the forebrain axonal connections. , 2002, Development.

[12]  J. Pevsner,et al.  Postmortem brain abnormalities of the glutamate neurotransmitter system in autism , 2001, Neurology.

[13]  K Nakabayashi,et al.  Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31. , 2001, Genomics.

[14]  Stephen J. Guter,et al.  A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. , 2001, American journal of human genetics.

[15]  S. Folstein,et al.  Evidence supporting WNT2 as an autism susceptibility gene. , 2001, American journal of medical genetics.

[16]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Worley,et al.  Regulation of SSAT expression by synaptic activity , 2001, The European journal of neuroscience.

[18]  T. Wassink,et al.  Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder , 2001, Molecular Psychiatry.

[19]  Steve D. M. Brown,et al.  A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse , 2000, Nature Genetics.

[20]  S. Scherer,et al.  Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. , 2000, American journal of human genetics.

[21]  Stuart K. Calderwood,et al.  HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine , 2000, Nature Medicine.

[22]  S. Folstein,et al.  An autosomal genomic screen for autism. , 1999, American journal of medical genetics.

[23]  S. Folstein,et al.  An autosomal genomic screen for autism. Collaborative linkage study of autism. , 1999, American journal of medical genetics.

[24]  Courtney A. Harper,et al.  A genomic screen of autism: evidence for a multilocus etiology. , 1999, American journal of human genetics.

[25]  M. Ross,et al.  Cerebellar histogenesis is disturbed in mice lacking cyclin D2. , 1999, Development.

[26]  Christopher Gillberg,et al.  Genome-Wide Scan for Autism Susceptibility Genes , 1999 .

[27]  Christopher Gillberg,et al.  Chromosomal Disorders and Autism , 1998, Journal of autism and developmental disorders.

[28]  Stephen J. Guter,et al.  Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. , 1998, American journal of human genetics.

[29]  W. Singer,et al.  Differential patterns of semaphorin expression in the developing rat brain , 1998, The European journal of neuroscience.

[30]  C. Francks,et al.  A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. , 1998, Human molecular genetics.

[31]  J. McPherson,et al.  Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval. , 1998, Biochemical and biophysical research communications.

[32]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[33]  R. Adams,et al.  A novel class of murine semaphorins with homology to thrombospondin is differentially expressed during early embryogenesis , 1996, Mechanisms of Development.

[34]  J. Bernal.  Thyroid hormones and brain development. , 1995, Vitamins and hormones.

[35]  P Bolton,et al.  Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. , 1995, American journal of human genetics.

[36]  A. Bailey,et al.  Autism as a strongly genetic disorder: evidence from a British twin study , 1995, Psychological Medicine.

[37]  A. Couteur,et al.  Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders , 1994, Journal of autism and developmental disorders.

[38]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[39]  C. Gillberg,et al.  A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. , 1989, Journal of child psychology and psychiatry, and allied disciplines.

[40]  E. Schopler,et al.  Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS) , 1980, Journal of autism and developmental disorders.

[41]  S. Folstein,et al.  Infantile autism: a genetic study of 21 twin pairs. , 1977, Journal of child psychology and psychiatry, and allied disciplines.

[42]  J. Buxbaum,et al.  Association between a GABRB3 polymorphism and autism , 2002, Molecular Psychiatry.

[43]  C. Gillberg,et al.  Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. , 1999, Human molecular genetics.

[44]  J. Dussault,et al.  Thyroid hormones and brain development. , 1987, Annual review of physiology.

[45]  L. Kanner.  Autistic disturbances of affective contact. , 1968, Acta paedopsychiatrica.