The Dopamine D 4 Receptor Gene

terminal, diffuses across the synaptic cleft, and binds to specific dopamine receptors on the plasma membrane of the postsynaptic terminal. Five distinct dopamine receptors have now been cloned, each produced by a different gene (D1–D5 receptors). These different genes presumably arose by gene duplication millions of years ago, and significant differences in their signaling properties have evolved over time. Two general classes have emerged based on pharmacological studies: the D1 and D5 receptors generally transmit stimulatory signals, whereas the D2–D4 receptors are inhibitory. In addition to these five separate dopamine genes, individual receptors may vary to some extent between different populations and individuals. These differences ultimately are based on differences in the nucleotide sequences that also emerged over millions of years of evolution. The differences in nucleotide sequences can now be directly determined in the laboratory by sequencing of the gene in question. Obviously, when the sequences in a gene from two individuals are compared, differences in the sequences will emerge. These changes in sequences are termed polymorphisms. Polymorphisms may occur as single base substitutions, as deletions or insertions, or as multiple repetitions of a particular sequence of base pairs (bp). This last type of polymorphism was the first polymorphism discovered within the DRD4 gene, and it turned out to be a 48-bp repeated sequence. The interest in polymorphisms arose when it was realized that they could be used as markers to help localize genes that cause or contribute to the expression of a particular illness. For example, if a particular polymorphism is found to be passed on to the next generation and all individuals who received that polymorphism develop a specific disease, then the investigators would have considerable evidence that either that particular gene or one that lies very close to it is responsible for the symptoms. This is in fact the basis for genetic linkage studies (Pauls, 1999). Polymorphisms may, or may not, change the functional properties of the protein in which they occur. Whether the enzymatic properties of a protein are affected depends on where the nucleotide changes occur within the gene. Changes to the coding region of a gene are more likely to have functional consequences, as many of these nucleotide changes will alter the amino acid sequence of the protein. Changes outside of the coding region of a gene are less likely to have an effect on the enzymatic activity as they are less likely to change its amino acid structure. There are times, however, when even a polymorphism outside of the coding region has a dramatic effect on the protein’s functioning. This occurs, for example, when the polymorphism arises within the promoter region and affects the amount of transcription, either increasing or decreasing the amount of message produced. Another example is when the polymorphism falls within an intron and alters the nucleotide sequence that regulates the correct splicing of the RNA message. Since the cloning of the gene for the dopamine D4 receptor (DRD4 ) in 1991 (Paterson et al., 1999), it has received considerable attention in genetic studies. Much of the original research focused on the possible role of the D4 receptor gene in schizoGenetics of Childhood Disorders: XXII. ADHD, Part 6: The Dopamine D4 Receptor Gene