Functional effects of a tandem duplication polymorphism in the 5′flanking region of the DRD4 gene

Background Several polymorphisms have been identified in the 5′flanking region of the human dopamine D4 receptor gene (DRD4), including a tandem duplication polymorphism. This comprises a 120-base-pair repeat sequence that is known to have different allele frequencies in various populations around the world. Furthermore, various studies have revealed evidence of linkage to attention-deficit/hyperactivity disorder and association with schizophrenia and methamphetamine abuse. The location of the polymorphism in the 5′regulatory region of the DRD4 gene and the fact that it consists of potential transcription factor binding sites suggest that it might confer differential transcriptional activity of the alleles. Methods We investigated the functional effects of this gene variant with transient transfection methods in four human cell lines and then assessed transcriptional activity with luciferase reporter gene assays. Results The longer allele has lower transcriptional activity than the shorter allele in SK-N-MC, SH-SY5Y, HEK293, and HeLa cell lines. Conclusions This evidence suggests that the duplication might have a role in regulating the expression of the DRD4 gene and provides an understanding of the biological mechanisms underlying the etiology of neuropsychiatric disorders such as ADHD, schizophrenia, and metamphetamine abuse