Linkage and association of the glutamate receptor 6 gene with autism - PubMed (original) (raw)

Linkage and association of the glutamate receptor 6 gene with autism

S Jamain et al. Mol Psychiatry. 2002.

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 eight 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.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Maternal, paternal and combined LOD scores at each marker along the chromosome 6q21 region calculated by ASPEX.

Figure 2

Figure 2

Structure of the human GluR6 gene. a. Genomic organisation of the human GluR6 gene. Exon sequences were identified by BLAST analysis, using the human GluR6 cDNA sequence (NM_021956) and three genomic sequences (AP002528, AP002529, AP002530); b. Predicted exon-intron dsRNA around the Q/R editing site (intron 12 containing the ECS) of GluR6 pre-mRNA by the RNA mfold software. The nucleotides of intron 12 omitted from presentation are indicated in the loop.

Figure 3

Figure 3

Sequence analysis and isoforms of the human GluR6 transcript, a. Location of all SNPs identified in this study, b. Conservation of the Methionine 867 in different species and location of the protein kinase C (PKC) phosphorylation consensus site; c. RT-PCR performed on human hippocampus (h), amygdala (a) and whole brain (wb) RNA; forward primers were chosen in exon 15, 15bis or 15ter; the reverse primer is the same for all PCRs and is located in exon 16. d. C-terminal protein sequences of the different GluR6 isoforms.

Similar articles

Cited by

References

    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4. American Psychiatric Press; Washington DC: 1994.
    1. Kanner L. Autistic disturbances of affective contact. Nerv Child. 1943;2:217–250. - PubMed
    1. Gillberg C, Wing L. Autism: not an extremely rare disorder. Acta Psychiatr Scand. 1999;99:399–406. - PubMed
    1. Miles JH, Hillman RE. Value of a clinical morphology examination in autism. Am J Med Genet. 2000;91:245–253. - PubMed
    1. Ritvo ER, Freeman BJ, Pingree C, Mason-Brothers A, Jorde L, Jenson WR, et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am J Psychiatry. 1989;146:194–199. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources