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Linkage and association of the glutamate receptor 6 gene with autism

Journal article
Authors Stéphane Jamain
Catalina Betancur
Hélène Quach
Anne Philippe
Marc Fellous
Bruno Giros
Christopher Gillberg
Marion Leboyer
Thomas Bourgeron
Published in Molecular Psychiatry
Volume 7
Issue 3
Pages 302-310
ISSN 1359-4184
Publication year 2002
Published at Institute for the Health of Women and Children, Dept of Child and Adolescent Psychiatry
Pages 302-310
Language en
Links www.ncbi.nlm.nih.gov/pmc/articles/P...
Keywords Amino Acid Sequence, Autistic Disorder, Genetics, Brain, Physiopathology, Child, Chromosome Mapping, Chromosomes, Human, Pair 6, Exons, Family, Female, Genetic Linkage, Genetic Markers, Genotype, Glutamic Acid, Physiology, Humans, Male, Molecular Sequence Data, Open Reading Frames, Receptors, Kainic Acid, Genetics, Restriction Mapping
Subject categories Child and adolescent psychiatry, Psychiatry, Medical and Health Sciences

Abstract

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in 8 new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

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