THE D5 DOPAMINE-RECEPTOR GENE IN SCHIZOPHRENIA - IDENTIFICATION OF A NONSENSE CHANGE AND MULTIPLE MISSENSE CHANGES BUT LACK OF ASSOCIATION WITH DISEASE

To determine whether mutations in the D5 dopamine receptor gene (DRD5) are associated with schizophrenia, the gene was examined in 78 unrela ted schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fi ngerprinting (ddF), a screening method related to single strand confor mational polymorphism analysis that detects essentially 100% of mutati ons. All samples with abnormal ddF patterns were sequenced. Nine diffe rent sequence changes were identified. Five of these were sequence cha nges that would result in protein alterations; of these, one was a non sense change (C335X), one was a missense change in an amino acid conse rved in all dopamine receptors (N351D), two were missense changes in a mino acids that are identical in only some dopamine receptors and in o nly some species (A269V; S453C), and one was a missense change in a no n-conserved amino acid (P330Q). To investigate whether the nonsense ch ange (C335X), predicted to prematurely truncate the receptor protein a nd result in a 50% diminution of functional protein, was associated wi th schizophrenia, other neuropsychiatric diseases, or specific neurops ychological, psychophysiological, or personality traits, both case-con trol and family analyses were performed. No statistically-significant associations were detected with schizophrenia or other neuropsychiatri c diseases. There also were no significant associations between any on e measure of neuropsychological function. However, a post-hoc analysis of combined measures of frontal lobe function hinted that heterozygot es for C335X may have a vulnerability to mild impairment, but these fi ndings must be interpreted with caution. In additional case-control an alyses, none of the other three missense changes that occurred in evol utionarily conserved amino acids (A269V, N351D, S453C) was found to be associated with schizophrenia.