A Ser311Cys Mutation in the Human Dopamine Receptor D2 Gene Is Associated With Reduced Energy Expenditure

Abstract

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P ‫؍‬ 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P ‫؍‬ 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake. Diabetes 50:901-904, 2001

Food reinforcement and eating: A multilevel analysis.

“…Individuals with genotypes containing either one or two copies of the A1 allele have fewer D2 receptors than have those lacking an A1 allele and so are associated with reduced brain dopamine signaling (Jonsson et al, 1999;Pohjalainen et al, 1998;Ritchie & Noble, 2003). In genetically homogeneous populations, such as the Pima Indians, a missense substitution in the DRD2 gene has been associated with reduced resting energy expenditure (Tataranni et al, 2001), greater BMI, and type II diabetes (Jenkinson et al, 2000). Epidemiological studies in genetically heterogeneous human populations have demonstrated a higher prevalence of the A1 DRD2 allele in obese individuals (~50%) compared with lean individuals (~30%; Blum et al, 1996;Comings et al, 1993;Comings, Gade, MacMurray, Muhleman, & Peters, 1996;Noble et al, 1994).…”

“…The absence of DRD2 produces profound bradykinesia and hypothermia in mice (Baik et al, 1995). In humans, a mutation of the DRD2 gene that impairs D2 receptor function is associated with lower total and 24-hour resting energy expenditure and greater BMI in Pima Indians (Tataranni et al, 2001). Polymorphisms of the DRD2 gene have been associated with reported yearly physical activity levels in white female subjects (Simonen et al, 2003).…”

Socioeconomic stress by dopamine receptor 2 gene interactions in the development of obesity

“…In the Pima Indian population, a missense substitution in the DRD2 gene has been associated with resting energy expenditure (Tataranni, et al, 2001), greater BMI and type II diabetes (Jenkinson, et al, 2000). Several population studies have documented an association between reduced DRD2 expression (viz.…”

Retraction Notice to: <i>DRD2/ANKK1</i> gene polymorphism rs1800497 is associated with exercise habit in the period from childhood to adolescence in Japanese

“…Sev-*Correspondence: haruka-m@nih.go.jp eral studies in rodents have suggested that the dopamine signal system may be associated with voluntary PA [23][24][25] . In humans, several studies have shown an association between DRD2 gene polymorphisms and PA level over the past year (vs. rs6275) 17) and 24-h resting energy expenditure (vs. rs1801028) 18) . The DRD2/ANKK1 TaqIA polymorphism (rs1800497, C > T) in the ANKK1 (ankyrin repeat and protein kinase domain-containing protein 1) gene is located 10 kb downstream from the DRD2 gene 26) .…”

“…In addition, it has been reported that genetic factors peaked in their contribution to exercise behavior around ages 19-20 at about 80% 10) . To explore the genetic factors related to PA level or exercise behavior, several candidate genes, including the melanocortin-4 receptor gene [11][12][13] , the leptin receptor gene 14,15) , and the dopamine receptor gene [16][17][18][19] , have been examined, and a genome-wide association study for exercise behavior was also conducted 20) . However, it is still not clear which gene(s) or genotype(s) are responsible for individual differences in PA level or exercise behavior.…”