Dopamine D3 receptor gene: Organization, transcript variants, and polymorphism associated with schizophrenia

Abstract

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR‐based method was developed for genotyping this polymorphism. The distributions of the Msp I and Bal I genotypes were not independent in 297 individuals (x2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (x2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM‐III‐R chronic schizophrenics and 85 controls (x2 = 5.3, df = 1, P = 0.02) and found more important in males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (x2 = 0.06, df = 1, P = 0.80, x2 = 0.22, df = 1, P = 0.90 and x2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms. © 1996 Wiley‐Liss, Inc.

Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia

“…In addition, the sample used in the present (ISHDSF) study is strongly familial and therefore should have easily detected the effect. As with the Welsh sample, the French sample was also subsequently enlarged, 9 but the strength of the original association reported in Crocq et al 10 (Chi-square = 6.96, d.f. = 1, P = 0.008) was weakened (Chi-square = 5.3, d.f.…”

“…The gene is mapped to chromosome 3q13.3; the coding sequence is 661 bp in length and contains six exons. 9 Association studies of DRD3/MscI polymorphism (Serine-9-Glycine substitution) and schizophrenia have produced interesting but conflicting findings. In a study of Welsh and French schizophrenic patients, significant association was observed between the disease and homozygosity for DRD3 variants 1-1 and 2-2.…”

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

“…The single gene coding for the D3 receptor is organized to allow for the production of different transcripts via alternative splicing of D3 receptor heteronuclear-RNA (hn RNA or pre-mRNA) in the cell nucleus, as illustrated in Figure 1 (Griffon et al, 1996;Fu et al, 1995;Giros et al, 1991;Park et al, 1995). At least seven distinct alternatively spliced D3 receptor variants are produced, including the full-length D3 receptor (called 'D3'), and a shorter receptor isoform, D3S, lacking 21 amino acids within the third cytoplasmic loop (Fishburn et al, 1993).…”

Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

“…[60][61][62][63] Primers and conditions used for amplification of the d4 receptor were as previously published. 32 In addition, primers were not designed within known polymorphic coding regions such as for the 5ht2a and 5ht6 receptors.…”