Alternative titles; symbols
HGNC Approved Gene Symbol: DRD4
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:637,269-640,706 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | {Attention deficit-hyperactivity disorder} | 143465 | Autosomal dominant | 3 |
| Autonomic nervous system dysfunction | 3 |
DRD4 is a G protein-coupled receptor that belongs to the dopamine D2-like receptor family. Functionally, the D2-like receptors are characterized by their ability to inhibit adenylyl cyclase (Oldenhof et al., 1998).
Van Tol et al. (1991) cloned the gene for the human dopamine D4 receptor. DRD4 encodes a putative 387-amino acid protein with 7 transmembrane domains, a potential N-linked glycosylation site, and several putative phosphorylation sites. It shares 28%, 41%, and 39% sequence homology with DRD1 (126449), DRD2 (126450) and DRD3 (126451), respectively. Northern blot analysis revealed a 5.3-kb DRD4 mRNA in a human neuroblastoma cell line and in several regions of the brain in rat and monkey. Relatively high levels of DRD4 were observed in the monkey frontal cortex, midbrain area, amygdala, and medulla, with lower levels in the basal ganglia.
Van Tol et al. (1992) identified 3 cDNA clones of DRD4 that differed from each other in a 48-bp sequence in the putative third cytoplasmic loop. The sequence occurred as a direct repeat sequence (D4.2), as a 4-fold repeat (D4.4), or as a 7-fold repeat (D4.7). The deduced amino acid sequences of the clones implied the existence of 3 different forms of the receptor with a variably sized putative third cytoplasmic loop. In a note added in proof, Van Tol et al. (1992) stated that they had identified 2 additional allelic forms of the DRD4 gene corresponding in size with a 3- and 5-fold repeat sequence.
Van Tol et al. (1991) determined that the DRD4 gene contains 4 exons. Van Tol et al. (1992) identified a 48-bp sequence in exon 3 of the DRD4 gene that contained a variable number of tandem repeats (VNTR).
Using a probe for DRD4 that recognizes an informative HincII polymorphism, Gelernter et al. (1991, 1992) studied linkage to DNA markers in non-CEPH families. Linkage was found to tyrosine hydroxylase (191290; lod = 7.4 with male and female recombination = 0.10 and 0.17, respectively) and with the Harvey RAS oncogene (190020; lod = 11.1 with male and female recombination = 0.02 and 0.0, respectively). Their observations suggested that DRD4 is close to and probably distal to HRAS, placing DRD4 in 11p15.5. By further linkage studies, Petronis et al. (1993) determined that the DRD4 gene lies proximal to HRAS.
Van Tol et al. (1991) found that the affinity of DRD4 for the antipsychotic clozapine was much higher than that of DRD2 and DRD3.
Van Tol et al. (1992) showed that expression of 3 variant forms of DRD4 showed different properties for the long form (D4.7) as contrasted with the shorter forms with respect to clozapine and spiperone binding. They suggested that variations in the 48-bp sequence in the third cytoplasmic loop of DRD4 among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication.
In vitro studies suggested that the receptor encoded by the DRD4 7R allele may be subsensitive to endogenous dopamine compared with the receptor encoded by the 2R allele (Asghari et al., 1995), although this was apparently not due merely to the length of the third intracellular loop (Jovanovic et al., 1999).
Seeman et al. (1993) found a selective 6-fold increase in the density of dopamine D4 receptors in the brains of patients with schizophrenia (see 181500).
Oldenhof et al. (1998) showed that a proline-rich region within the putative third cytoplasmic loop interacts in vitro with a variety of SH3 domain-containing proteins, including GRB2 (108355) and NCK (see 600508). Deletion of all putative SH3-binding domains in this region resulted in constitutive internalization of the receptor.
Gong et al. (2003) described a large-scale screen to create an atlas of CNS gene expression at the cellular level and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes, and pathways. They observed that Drd4 BAC transgenic lines expressed at high levels in the prefronal cortex. At high magnification, these cells were identified as layer 5 pyramidal cells.
Using a yeast 2-hybrid assay, Rondou et al. (2008) showed that KLHL12 (614522) interacted with D4.2, D4.4, and D4.7, but not with other dopamine receptors tested and not with mouse D4, which lacks the polymorphic repeat in IC3. Domain mapping showed that the IC3 domain of D4 and the kelch repeat domain of KLHL12 were required for the interaction. Immunoprecipitation analysis revealed that KLHL12 interacted with the CUL3 (603136) E3 ubiquitin ligase complex via direct interaction with CUL3 and, possibly, ROC1 (RBX1; 603814). Binding of KLHL12 to both D4 and CUL3 resulted in recruitment of D4 to the ubiquitin ligase complex, leading to D4 ubiquitination. Knockdown of KLHL12 in KLHL12-overexpressing HEK293 cells abolished association of D4 with CUL3, and knockdown of CUL3 decreased ubiquitination of D4.
Most of the diversity in the DRD4 gene is the result of length and single-nucleotide polymorphism (SNP) variation in the 48-bp VNTR in exon 3, which encodes the third intracellular loop of the receptor. Variant alleles containing 2 (2R) to 11 (11R) repeats are found, with the resulting proteins having 32 to 176 amino acids at this position. The frequency of these alleles varies widely. The 7R allele, for example, has an exceedingly low incidence in Asian populations yet a high frequency in the Americas (Chang et al., 1996).
Chang et al. (1996) presented data that urged caution in the interpretation of DRD4 association studies in mixed populations. They focused particularly on the expressed polymorphism in exon 3, which may have functional relevance. The polymorphism (an imperfect 48-bp tandem repeat coding for 16 amino acids; alleles had been reported with 2 to 10 repeats) was found to be universal, suggesting that it is ancient and arose before the global dispersion of modern humans. They described diversity of allele frequencies for this expressed polymorphism among different populations and emphasized the importance of population considerations in the design and interpretation of association studies using the polymorphism.
Association with Attention Deficit-Hyperactivity Disorder
Attention deficit-hyperactivity disorder (ADHD; 143465) is a developmental syndrome expressed along 3 domains: inattention, hyperactive-impulsive, and combined type. Several investigations examined the role of the DRD4 exon 3 repeat polymorphism in ADHD. The long 7R allele of this receptor was shown in population-based and family-based studies (LaHoste et al., 1996; Rowe et al., 1998; Smalley et al., 1998; Swanson et al., 1998), but not in 1 case-control design (Castellanos et al., 1998), to be a risk factor for this disorder. In a family-based study of the DRD4 exon 3 repeat region and ADHD, Eisenberg et al. (2000) failed to observe preferential transmission of the DRD4 7R allele, and there was no preferential transmission observed when genotypes were compared. The reasons for the conflict with earlier findings were discussed.
Swanson et al. (2000) evaluated ADHD subgroups defined by the presence or absence of the 7R allele of the DRD4 gene, using neuropsychologic tests with reaction time measures designed to probe attention networks with neuroanatomic foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7R-present subgroup showed normal speed and variability of response, whereas the average reaction times of the 7R-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7R-present subgroup seemed to be free of some of the neuropsychologic abnormalities thought to characterize ADHD. These findings led Swanson et al. (2000) to reconceptualize the possible association of the DRD4 gene with ADHD.
Ding et al. (2002) stated that 8 separate replications of the initial observation of an increased frequency of the DRD4 7R alleles in ADHD probands had been reported.
Langley et al. (2004) found that in children with ADHD, possession of the DRD4 7R allele appeared to be associated with an inaccurate, impulsive response style on neuropsychologic tasks that was not explained by ADHD symptom severity. Children with the 7R allele had significantly more incorrect responses and shorter mean reaction times for incorrect responses, and displayed higher activity levels as measured by actigraphy compared to children without the allele.
Lynn et al. (2005) investigated the link between ADHD in adults, novelty-seeking temperament, and the DRD4 7R allele in 171 parents from 96 families with ADHD-affected sib pairs. Of the parents, 56 (33%) had a lifetime history of ADHD with 28 (50%) continuing to meet DSM-IV criteria. Novelty seeking and the 7R variant were associated with a lifetime history of ADHD; however, novelty seeking and ADHD did not appear to be due to the DRD4 7R variant.
Leung et al. (2005) noted that the DRD4 7R allele associated with ADHD varies in prevalence across ethnic groups and is very low in Asian populations. Leung et al. (2005) studied 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate responders and observed no evidence of 7R alleles. Instead, they found a 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically matched controls (20%) (p = 0.015). This 1.65-fold increase in the 2R allele was close to the increase of the 7R allele observed in ADHD children of European ancestry. Leung et al. (2005) postulated that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD.
Manor et al. (2002) noted that polymorphisms (specifically the short exon 3 allele) of the DRD4 gene have been associated with ADHD in some studies, but that 2 Israeli studies (Eisenberg et al., 2000; Kotler et al., 2000) failed to observe this association. Manor et al. (2002) studied 178 Israeli triads using the transmission disequilibrium test (TDT). Preferential transmission of the short allele was associated with ADHD. Study of the same triad using the Test of Variables of Attention (TOVA) revealed that individuals with the short allele of the exon 3 repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. A dosage effect was observed in that increasing repeat size was accompanied by a reduced number of errors of commission and a significant difference was observed between the 2 versus 7 repeats.
McCracken et al. (2000) found significant preferential transmission of a 240-bp (long) allele of the DRD4 120-bp repeat promoter polymorphism (126452.0003) in 371 children with ADHD, and further analyses strengthened the evidence for linkage.
D'Souza et al. (2004) studied the function of the 120-bp tandem duplication sequence of the DRD4 gene by using transient transfection in 4 human cell lines and luciferase reporter gene assays. The longer allele had lower transcriptional activity than the shorter allele. Lower levels of transcriptional activity observed with the long form of the polymorphism could result in lower levels of expression of the DRD4 gene which may affect levels of dopamine in the synaptic cleft. The authors noted that their findings supported the hypothesis of McCracken et al. (2000) that the 240-bp allele was a risk factor for ADHD.
The Attention Network Test (ANT) uses the flanker task to measure conflict and shows strong activation in the dorsal anterior cingulate on neuroimaging studies. Because the cingulate is modulated by the ventral tegmental dopamine system, Fossella et al. (2002) tested 200 normal individuals with the ANT and genotyped them for 4 genes related to the dopamine system. Polymorphisms in the DRD4 and MAOA (309850) genes were significantly related to the efficiency of conflict. To examine whether this genetic variation contributed to differences in brain activation within the anterior cingulate cortex, Fan et al. (2003) genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the ANT. In each of the 2 genes they identified a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The 2 polymorphisms were the -1217G insertion/deletion in the upstream region of DRD4 and a 3-repeat allele of the 30-bp repeat in the MAOA promoter (309850.0002). The results demonstrated how genetic differences among individuals can be linked to individual differences in neuromodulators and in the efficiency of the operation of an appropriate attentional network.
Association with Novelty-Seeking Personality Trait and Risk-Taking Behavior
Human personality traits that can be reliably measured by rating scales show a considerable heritable component. One such instrument is the tridimensional personality questionnaire (TPQ), which was designed by Cloninger et al. (1993) to measure 4 distinct domains of temperament--novelty seeking (601696), harm avoidance, reward dependence, and persistence--that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger et al. (1993) proposed that individual variations in the novelty seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ novelty seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered, and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered, and frugal.
In a study of 20 abstinent alcohol-dependent men, a significant correlation was found between apomorphine-induced growth hormone release and the 'novelty seeking' score of the individual (Wiesbeck et al., 1995). This supported Cloninger's hypothesis by giving neuroendocrine evidence that this personality dimension is related to dopaminergic activity, albeit in the tuberoinfundibular dopaminergic system which is not directly associated with human personality traits.
Benjamin et al. (1996) pointed out that the possibility of a causal relationship between DRD4 and novelty seeking is supported by studies showing that the number of exon 3 repeats can affect the binding of ligands to the receptor; that DRD4 is expressed in limbic areas involved in cognition and emotion; that dopamine mediates exploratory behavior in experimental animals; that the rewarding effects of amphetamines and cocaine are related to dopamine release; and that novelty seeking is low in dopamine-deficient patients with Parkinson disease (168600).
In a group of 124 unrelated Israeli subjects, Ebstein et al. (1996) showed that higher than average novelty seeking test scores were significantly associated with a particular exonic polymorphism, the 7-repeat (7R) allele, in exon 3 of the DRD4 gene. The association of high novelty seeking and the 7R allele was independent of ethnicity, sex, or age of the subjects. These results were corroborated by Benjamin et al. (1996) who investigated the relationship between DRD4 exon 3 sequence variants and personality test scores in a population of 315 mostly male sibs, other family members and individuals in the United States. The association between long alleles of exon 3 and personality traits related to novelty seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than a population stratification.
In 2 groups of Finnish subjects (193 psychiatrically screened normal controls and 138 alcoholic offenders), Malhotra et al. (1996) determined DRD4 genotypes and assessed novelty seeking with the TPQ. In the control individuals, they found no significant association between novelty seeking and the 7R allele despite similar allele frequencies and the use of the same personality measure as employed by Ebstein et al. (1996). The group of alcoholic offenders had significantly higher novelty seeking than control individuals; however, Malhotra et al. (1996) could not replicate the previous association in this group. They suggested that DRD4 may require reevaluation as a candidate gene for personality variation.
Gelernter et al. (1997) also could not replicate an association between the 7-repeat allele (called DRD4*7R by them) and higher novelty seeking. They raised the possibility that this might represent a false negative. They concluded that if genetic variation at the DRD4 locus exerts an effect on human novelty seeking, it is likely to be through a mutation in linkage disequilibrium with the exon 3 VNTR rather than as a direct consequence of that variation.
Using the Japanese version of the Temperament and Character Inventory questionnaire, Tomitaka et al. (1999) studied the association between novelty seeking and the long alleles of the polymorphic exon 3 repeat sequence of DRD4 in 69 medical students and residents (average age of 25) of the Tokyo Women's Medical College Hospital. Although the long alleles of DRD4 were low in the Japanese population, the authors found an association between the long alleles and novelty seeking when compared to short alleles (p less than 0.014). The scores for exploratory excitability and extravagance were significantly higher in subjects with the long allele.
Kluger et al. (2002) conducted a metaanalysis of 20 studies, with a total of 3,907 individuals, involving the association between DRD4 polymorphisms and novelty seeking. Thirteen reports suggested that the presence of longer alleles is associated with higher novelty seeking scores and 7 reports suggested the opposite. Kluger et al. (2002) concluded that, on average, there was no association between DRD4 polymorphism and novelty seeking (average d = 0.06, 95% CI +/- 0.09). They found that there was true heterogeneity among the studies (i.e., unknown moderators exist), but that the strength of the association between DRD4 polymorphisms and novelty seeking in the presence of any moderator was likely to be weak. Kluger et al. (2002) also reported that a search for moderators had not yielded any reliable explanation for the variability among studies.
De Luca et al. (2001) presented evidence indicating that there is a genetic influence of the DRD4 gene on human temperament at birth and at 1 month of age. On assessment at 5 months of age, differences were not detected, denoting a strong environmental effect. De Luca et al. (2003) presented a follow-up, assessing the previously genotyped children at 3 years of age. By this age, both positive and negative emotions were more clearly differentiated than at 1 and 5 months of age. Moreover, exploratory behavior was more explicit at 3 years, given the increased competence of 3-year-old infants to explore the environment actively and intentionally. The study corroborated only in part previous results of a link between the DRD4 gene and human temperament. None of the extraversion and/or exploratory behavior measures was related to the long form of the DRD4 exon 3 repeat polymorphism, an unusually variable repeat region in the third cytoplasmic loop of the receptor that varies between 2 and 10 repeats in most populations and changes the length of the receptor protein (Asghari et al., 1995).
Savitz and Ramesar (2004) reviewed the evidence that alleles of the SERT (182138) and DRD4 genes impact variations in personality. They argued for the existence of a genuine effect: a gene-personality relationship rendered periodically latent through genetic epistasis, gene-environment interactions, variation in genetic background, and the presence of other variables.
In a study of financial risk taking of 94 young men assessed through a game with real monetary payoffs, Dreber et al. (2009) found an association between the 7R allele polymorphism in the DRD4 gene and increased financial risk-taking (see 601696). The DRD4 polymorphism was estimated to account for about 20% of the heritable variation in financial risk-taking. The findings were consistent with evolutionary selection for this allele for behaviors associated with migration and male competition, which entail an element of risk.
Among 65 individuals, Kuhnen and Chiao (2009) found that carriers of the DRD4 7R allele took 25% more risk in a financial investment risk game compared to individuals lacking the 7R allele. The authors speculated that financial risk-taking may result from evolutionarily adaptive mechanisms that encourage novelty-seeking behavior.
Association with Alcoholism
The ALDH2*2 allele of the aldehyde dehydrogenase-2 gene (100650.0001) is considered to be a genetic deterrent for alcoholism; however, Muramatsu et al. (1996) found that 80 of 655 Japanese alcoholics had the mutant allele. They postulated that these alcoholics had some other factor which overcame the adverse effects of acetaldehydemia and that this factor might reside in the 'reward system' of the brain in which dopamine plays a crucial role. Therefore, Muramatsu et al. (1996) studied variation at the DRD4 locus and found in the alcoholics a higher frequency of a 5-repeat (5R) allele of the DRD4 receptor 48-bp repeat polymorphism in alcoholics with ALDH2*2 than in 100 other alcoholics and 144 controls. They found that alcoholics with the 5R allele also abused other drugs more often.
Association with Mood Disorders
Using the Cockrane Review Manager, Lopez Leon et al. (2005) conducted a metaanalysis to reevaluate the role of DRD4 polymorphisms in mood disorders. In 917 patients with unipolar or bipolar affective disorder (see 125480) and 1,164 control individuals from 12 samples, an association was found between the DRD4 2R allele and unipolar depression (p less than 0.001) and unipolar and bipolar depression combined (p less than 0.001).
The 48-bp tandem repeat polymorphism in the coding region of DRD4 shows 4 repeats (4R) as the most common allele, with rarer variants containing 2 to 11 repeats (Chang et al., 1996). Ding et al. (2002) showed by DNA resequencing and haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of the 2R to 6R alleles can be explained by simple 1-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than 6 recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5- to 10-fold 'younger' than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, Ding et al. (2002) proposed that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection. Ding et al. (2002) estimated that the 7R allele may have originated approximately 40,000 years ago and that the appearance of radical new technology and/or the development of agriculture could be related to the increase in DRD4 7R allele frequency. They suggested that individuals with personality traits such as novelty seeking may have driven the expansion. In discussing why the 7R allele is associated with ADHD, Ding et al. (2002) speculated that the very traits that may be selected for in individuals possessing this allele may predispose to behaviors that are deemed inappropriate in the typical classroom setting.
To estimate directly haplotype diversity, Wang et al. (2004) resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the 48-bp tandem repeat DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibited little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intraallelic comparison at 18 high heterozygosity sites spanning the locus, they estimated that the 7R allele arose before the upper Paleolithic era (approximately 40,000-50,000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. Wang et al. (2004) proposed a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiologic differences between receptor variants.
Harpending and Cochran (2002) commented extensively on the mechanisms by which the increased frequency of the 7R allele might have occurred.
By homologous recombination, Rubinstein et al. (1997) created mice lacking the dopamine D4 receptor. Mutant mice were less active than wildtype controls in open field tests in both novel and familiar environments. However, mutant mice outperformed wildtype mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses indicated that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum of mutant mice. Rubinstein et al. (1997) proposed that DRD4 modulates normal, coordinated, and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.
Using an in silico search, followed by PCR, Hejjas et al. (2007) identified VNTR polymorphisms in genes of the dopaminergic system in 4 dog breeds and European gray wolves. Polymorphisms of the DRD4, DBH (609312), and DAT (SLC6A3; 126455) genes were associated with attention deficit, but not activity-impulsivity, in Belgian Tervuerens, a breed that had almost all genetic variants identified.
Nothen et al. (1994) identified a null mutation in the first exon of the DRD4 gene, predicted to result in a truncated nonfunctional protein. The mutation consisted of a 13-bp deletion of bases 235 to 247. The deletion was situated in the second transmembrane domain and included asp80, which is highly conserved within the family of catecholaminergic receptors and is postulated to act as counterion in catecholamine binding. The deletion altered the reading frame from amino acid 79 and generated a new stop codon 20 amino acids downstream. The mRNA was predicted to code for an aberrant protein of 98 amino acids with a calculated molecular mass of 11 kD. The frequency of the deletion was found to be about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric illnesses which included schizophrenia, bipolar affective disorder, and Tourette syndrome, indicating that heterozygosity for this mutation is not causally related to major psychiatric diseases. However, Nothen et al. (1994) identified an adult male who was homozygous for the mutation. He showed no symptoms of major psychiatric illness but displayed somatic ailments including acoustic neurinoma, obesity, and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein. The homozygous male was 50 years old at the time of study, had 4 children, and worked successfully as an engineer. Autonomic hyperactivity included severe dermatographism and excessive sweating, which occurred mainly during moderately warm temperatures and in social gatherings. The proband denied feelings of anxiety in these situations. Frequent fluctuations of pulse rate leading to intermittent sinus tachycardia and necessitating medication with a beta blocker had been recognized over the previous 10 years. A left-sided acoustic neurinoma (family history negative) had been operated on when he was 38; a second operation for recurrence was required 6 years later. He had been obese since adolescence. A reduced body temperature had repeatedly been measured (35.4 degrees C rectally).
Seeman et al. (1994) found a val194-to-gly variant of the dopamine D4 receptor in 12.5% of 186 Afro-Caribbeans but in none of 147 Caucasians tested. This variant, present in heterozygotes, was not associated with schizophrenia or any obvious dopamine-based disease. The amino acid substitution resulted from a T-to-G transversion. The amino acid replacement is 1 amino acid away from a serine that is critical for dopamine binding in the dopamine D2 receptor (126450). Liu et al. (1996) reported that the val194-to-gly DRD4 variant is 2 orders of magnitude less sensitive to dopamine, clozapine, and olanzapine than the normal receptor. The variant receptor was insensitive to guanine nucleotide, indicating the absence of a high-affinity state or functional state. They described a 15-year-old individual homozygous for this variant, who also had sickle cell disease. The patient had low weight and no axillary or pubic hair.
Seaman et al. (1999) identified a polymorphic tandem duplication of 120 bp located 1.2 kb upstream of the initiation codon of the DRD4 gene. McCracken et al. (2000) analyzed the DRD4 120-bp repeat promoter polymorphism in 371 children with attention deficit-hyperactivity disorder (143465) using the transmission disequilibrium test. The results showed a significant preferential transmission of the 240-bp (long) allele with ADHD, and further analyses strengthened the evidence for linkage.
Kustanovich et al. (2004) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD, including DRD4, and analyzed the results using the transmission disequilibrium test. The DRD4 120-bp insertion/deletion promoter polymorphism displayed a significant bias for transmission of the insertion. The DRD4 240-bp allele showed a significant association with ADHD in this sample, with an estimated genotype relative risk of 1.37.
In 2 independent population samples from North and South India, Juyal et al. (2006) found a significant association between Parkinson disease (PD; 168600) and the 120-bp duplication polymorphism (dup). Allelic analysis of 147 PD patients and 130 controls in the South Indian group yielded an odds ratio for disease development of 0.67 for the dup allele and 1.48 for the wildtype allele.
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