To determine whether mutations in the D5 dopamine receptor gene (DRD5) are associated with schizophrenia, the gene was examined in 78 unrelated schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fingerprinting (ddF), a screening method related to single strand conformational polymorphism analysis that detects essentially 100% of mutations. All samples with abnormal ddF patterns were sequenced. Nine different sequence changes were identified. Five of these were sequence changes that would result in protein alterations; of these, one was a nonsense change (C335X), one was a missense change in an amino acid conserved in all dopamine receptors (N351D), two were missense changes in amino acids that are identical in only some dopamine receptors and in only some species (A269V; S453C), and one was a missense change in a non-conserved amino acid (P330Q). To investigate whether the nonsense change (C335X), predicted to prematurely truncate the receptor protein and result in a 50% diminution of functional protein, was associated with schizophrenia, other neuropsychiatric diseases, or specific neuropsychological, psychophysiological, or personality traits, both case-control and family analyses were performed. No statistically-significant associations were detected with schizophrenia or other neuropsychiatric diseases. There also were no significant associations between any one measure of neuropsychological function. However, a post-hoc analysis of combined measures of frontal lobe function hinted that heterozygotes for C335X may have a vulnerability to mild impairment, but these findings must be interpreted with caution. In additional case-control analyses, none of the other three missense changes that occurred in evolutionarily conserved amino acids (A269V, N351D, S453C) was found to be associated with schizophrenia. / 1995 Oxford University Press.
Bibliographical noteFunding Information:
This work was supported in part by grants from the National Alliance for Research on Schizophrenia and Depression (NARSAD) (J.L.S.) and the National Institute of Mental Health (MH44276) (S.S.S.). The authors gratefully thank James Mitchell for assistance in the ascertainment of schizophrenic patients, David Hebrink and Paula Schmeling for ascertainment of control samples and DNA extraction, and David Hebrink for the performance of PASA assays. The cooperation of staff at the Zumbro Valley Mental Health Center (MN), the Anoka-Metro Regional Treatment Center (MN), the St. Peter Regional Treatment Center (MN), the Western State Hospital (WA), the Eastern State Hospital (WA) and the Dammasch State Hospital (OR) is greatly appreciated.