HGNC Approved Gene Symbol: UCP3
SNOMEDCT: 238136002, 83911000119104; ICD9CM: 278.01;
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:74,000,277-74,009,085 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | {Obesity, severe, and type II diabetes} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
Boss et al. (1997) and Vidal-Puig et al. (1997) described the cloning of UCP3 cDNAs. Both groups derived their clones from human skeletal muscle libraries, and both reported that UCP3 is approximately 57% and 73% identical to human UCP1 (113730) and UCP2 (601693), respectively. Boss et al. (1997) and Solanes et al. (1997) cloned a short isoform of UCP3 (UCP3S) containing 275 amino acids and a long isoform of UCP3 (UCP3L) containing 312 amino acids. UCP3S contains 3 mitochondrial energy-transfer-protein domains and 5 putative transmembrane domains, while UCP3L contains an additional 37 amino acids at its C terminus that encodes a putative transmembrane domain and a putative purine nucleotide-binding domain. Solanes et al. (1997) determined that UCP3S is generated when a cleavage and polyadenylation signal within the last intron prematurely terminates message elongation. Boss et al. (1997) used Northern blot analysis to show that in human tissue UCP3 is expressed as a 2.3-kb message in skeletal muscle and heart. In rat tissue, UCP3 transcripts were found in heart, brown adipose tissue, white adipose tissue, and skeletal muscle.
Boss et al. (1997) examined UCP expression in cold-adapted rats and found that, unlike UCP1, the expression levels of UCP2 and UCP3 were not affected by cold. Nonetheless, the authors concluded that UCP3 may be involved in thermogenesis through the uncoupling of oxidative phosphorylation in skeletal muscle.
Millet et al. (1997) observed an increase in the levels of UCP2 and UCP3 mRNA in skeletal muscle and adipose tissue from both lean and obese individuals undergoing fasting. They suggested that the increase indicates a role for these proteins in the metabolic adaptation to fasting. The similar induction of gene expression observed during fasting in lean and obese subjects show that there is no major alteration of UCP2 and UCP3 gene regulation in adipose tissue and skeletal muscle of obese subjects. UCP2 is widely expressed in human tissues, whereas UCP3 expression seems to be restricted to skeletal muscle, an important site of thermogenesis in humans.
With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. Bouchard et al. (1997) demonstrated linkage between markers at the UCP2/UCP3 region with resting metabolic rate. This region is syntenic to a region of mouse chromosome 7 that has been linked to hyperinsulinemia and obesity (Fleury et al., 1997).
Liu et al. (1998) and Hinz et al. (1999) showed that expression of UCP3 in yeast resulted in reduced cellular growth and a significant decrease in mitochondria membrane potential. Hinz et al. (1999) found that cellular respiration coupled to oxidative phosphorylation decreased, while cellular heat production increased. Liu et al. (1998) found that adenovirus-mediated leptin (164160) expression in obese ob/ob mice led to increased expression of Ucp3 in skeletal muscle, as well as significant weight loss.
UCP1 diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose by catalyzing a regulated leak of protons across the inner membrane. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Echtay et al. (2002) demonstrated that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2, and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. Superoxide-induced uncoupling correlates with the tissue expression of UCPs and appears in mitochondria from yeast expressing UCP1. Skeletal muscle mitochondria express only UCP3; therefore superoxide-induced uncoupling is absent in the skeletal muscle of UCP3 knockout mice. Echtay et al. (2002) concluded that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria.
In 9 healthy male volunteers, Hesselink et al. (2003) measured the phosphocreatine resynthesis rate following intense anoxic contraction, which is a sensitive index of in vivo mitochondrial function, after 7 days on a low-fat diet and again after 7 days on a high-fat diet. The high-fat diet increased UCP3 protein content in muscle by 44% compared to the low-fat diet, but this increase in UCP3 was not associated with any changes in the rate of muscle phosphocreatine resynthesis during conditions of maximal flux through oxidative phosphorylation. Hesselink et al. (2003) concluded that the primary role of UCP3 in humans is not uncoupling.
Solanes et al. (1997) determined that the UCP3 gene contains 7 exons and spans about 8.5 kb. The coding sequence uses exons 2 to 7 and spans about 5.25 kb.
The observation that UCP3 is increased in situations where fatty acid entry into the mitochondria may exceed the beta-oxidation capacity suggested to Russell et al. (2003) that this protein may be involved in the outward translocation of fatty acid from the mitochondrial matrix. The authors performed biochemical and molecular tests using muscle from patients with riboflavin-responsive multiple acyl-coenzyme A dehydrogenase deficiency (MADD; 231680), a lipid storage myopathy characterized by a decrease in fatty acid beta-oxidation capacity. The results demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see 157655) and II (see 600857), associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation.
By radiation hybrid analysis and PCR of P1 and BAC genomic clones, Solanes et al. (1997) mapped the UCP3 gene to chromosome 11q13, adjacent to the UCP2 gene. Walder et al. (1998) pointed out that the UCP2 and UCP3 genes constitute a cluster that maps to 11q13. Boss et al. (1998) described the genomic structure of the UCP3 gene and mapped the gene to 11q13 by somatic cell hybrid and radiation hybrid analysis. Pecqueur et al. (1999) determined that the UCP2 gene is located 7 kb downstream of the UCP3 gene.
By PCR of mouse P1 and BAC clones, Solanes et al. (1997) mapped the mouse Ucp3 and Ucp2 genes to chromosome 7.
Argyropoulos et al. (1998) identified a missense polymorphism in exon 3 (V102I; 602044.0001) of the UCP3 gene. A mutation introducing a stop codon in exon 4 (R143X; 602044.0002) and a terminal polymorphism in the splice donor junction of exon 6 (602044.0003) were also identified in an individual who was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6 splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wildtype individuals, implicating a role for UCP3 in metabolic fuel partitioning.
Brown et al. (1999) found that expression of native human UCP3 mutations in yeast showed complete loss (R70W; 602044.0004), significant reduction (R143X; 602044.0002), or no effect (V102I; 602044.0001 and +1G-A; 602044.0003) on the uncoupling activity of UCP3. The authors concluded that certain mutations in UCP3 alter its functional impact on membrane potential, possibly conferring susceptibility to metabolic diseases.
Dalgaard et al. (2001) tested whether variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-year follow-up among Danish subjects. Mutation screening of approximately 1 kb 5-prime upstream of the UCP3 gene revealed a C-to-T variant at -55 (rs1800849). The frequency of this polymorphism was evaluated by restriction fragment length polymorphism analysis in 4 groups: (1) a group of 744 obese Danish men who at the draft board examinations had a BMI of at least 31 kg/m2; (2) a randomly selected control group consisting of 857 draftees; (3) 258 middle-aged subjects; and (4) 409 sixty-year-old subjects. The frequency of the T allele was 26.0% among the obese draftees and 26.9% in the control group. The authors concluded that this variant does not play a major role in the development of common obesity among Danish subjects.
Clapham et al. (2000) created transgenic mice that overexpress human UCP3 in skeletal muscle. UCP3 expression was driven by the human alpha-skeletal actin (102610) promoter, limiting expression to skeletal muscle. Clapham et al. (2000) bred 3 independent lines to homozygosity and selected a line of mice that had a 66-fold increase in UCP3 expression. These mice were hyperphagic but weighed less than their wildtype littermates. Magnetic resonance imaging (MRI) showed a striking reduction in adipose tissue mass. The mice also exhibited lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. Clapham et al. (2000) concluded that their data provided evidence that skeletal muscle UCP3 has the potential to influence metabolic rates and glucose homeostasis in the whole animal. Choi et al. (2007) showed that transgenic mice that overexpress human UCP3 in skeletal muscle were completely protected against the fat-induced defects and insulin resistance developed in wildtype mice fed a high-fat diet. Protection was associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKC-theta (600448) activity.
Uncoupling protein-3 is a mitochondrial protein that can diminish the mitochondrial membrane potential. Levels of muscle UCP3 mRNA are increased by thyroid hormone and fasting. Gong et al. (2000) produced Ucp3 knockout mice to test the hypothesis that UCP3 influences metabolic efficiency and is a candidate obesity gene. The Ucp3 -/- mice had no detectable immunoreactive UCP3 by Western blot analysis. In mitochondria from the knockout mice, proton leak was greatly reduced in muscle, minimally reduced in brown fat, and not reduced at all in liver. These data suggested that UCP3 accounts for much of the proton leak in skeletal muscle. Despite the lack of UCP3, no consistent phenotypic abnormality was observed in the mice. They were not obese and had normal serum insulin, triglyceride, and leptin levels, with a tendency toward reduced free fatty acids and glucose. Knockout mice showed a normal circadian rhythm in body temperature and motor activity and had normal body temperature responses to fasting, stress, thyroid hormone, and cold exposure. The baseline metabolic rate and respiratory exchange ratio were the same in knockout and control mice, as were the effects of fasting, a beta-3 adrenergic agonist, and thyroid hormone on these parameters. The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp1 single knockout mice. The data suggested that Ucp3 is not a major determinant of metabolic rate but, rather, has other functions.
In Ucp3 knockout mice, Vidal-Puig et al. (2000) found that skeletal muscle mitochondria lacking Ucp3 are more coupled (i.e., increased state 3/state 4 ratio), indicating that Ucp3 has uncoupling activity. In addition, production of reactive oxygen species was increased in mitochondria lacking Ucp3. Despite these effects on mitochondrial function, Ucp3 did not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis.
Mills et al. (2003) found that mice deficient in Ucp3 have a diminished thermogenic response to the drug MDMA, also known as 'ecstasy,' and did not die from a dose of 40 mg kg(-1), which killed 30% of wildtype littermates. Although the baseline temperature of Ucp3 -/- mice was indistinguishable from that of wildtype animals, Ucp3-deficient mice showed a significantly blunted rise in both skeletal muscle and rectal temperature following MDMA administration. Mills et al. (2003) concluded that UCP3 is important in MDMA-induced hyperthermia.
In a Gullah-speaking African American woman with severe obesity (601665) and type II diabetes (125853), Argyropoulos et al. (1998) found heterozygosity for a val102-to-ile (V102I) mutation of the UCP3 gene, located in the first cytosol-oriented extramembranous loop. Three overweight children in this family were found to be homozygous for the V102I polymorphism. The fourth child, a 9-year-old male with a body mass index (BMI) of 18.5, was heterozygous for the V102I polymorphism. No paternal sample was available but the father was presumed to be at least heterozygous for the V102I polymorphism. The polymorphism was not found in genomic DNA from 128 Caucasian Americans. However, examination of 280 African Americans revealed that 4% of individuals were homozygous and 28% heterozygous for the polymorphism. In the Mende tribe in Sierra Leone, 3% of the population was found to be homozygous A/A and 21% heterozygous G/A.
In a 16-year-old with morbid obesity (601665) (BMI = 51.8) and type II diabetes (125853), Argyropoulos et al. (1998) found compound heterozygosity for a 427C-T transition in exon 4, resulting in the introduction of a premature stop codon at residue 143, arg143 to ter (R143X), in the third, matrix-oriented loop. In addition, the patient was heterozygous for a guanine to adenine polymorphism at the splice donor site of exon 6 (Ggt-Gat), resulting in loss of the splice junction and premature termination of the protein product in the sixth, matrix-oriented loop (602044.0003). A putative protein resulting from this mutation would be identical to that encoded by the short transcript of UCP3 mRNA. Pedigree analysis and DNA sequence determination of family members showed that the R143X mutation was transmitted to the compound heterozygous proband from the grandmother, through the mother, in typical mendelian fashion. The heterozygous polymorphism at the exon 6 splice donor junction (Ggt-Gat) was not detected in the maternal lineage and was most likely transmitted from the father, whose DNA was not available for analysis, but may have arisen as a new change. Argyropoulos et al. (1998) examined an additional 168 individuals comprising both African Americans and Caucasians for the 2 nucleotide changes. The R143X mutation was not detected in any other individual in either racial group. The exon 6 splice donor stop mutation, however, was detected in African-American subjects but not in Caucasians. An identical allele frequency (G, 90% and A, 10%) was found in Gullah-speaking African Americans and the Mende tribe. No homozygous subjects for the polymorphism (a/a) were detected in 287 Gullah-speaking African Americans and only 3 homozygotes were identified in 192 subjects of the Mende tribe. Haplotype analysis of 2 polymorphisms, V102I (602044.0001) and the exon 6 splice donor Ggt-Gat, showed that the 2 genotypes were independent.
In a 16-year-old female with morbid obesity (601665), Argyropoulos et al. (1998) found compound heterozygosity for a polymorphism at the exon 6 splice donor junction (Ggt-Gat) and the R143X mutation (602004.0002). The rare R143X mutation was inherited in the maternal line; the splice site polymorphism was presumably transmitted from the father. The g-to-a transition at the splice donor site of exon 6 resulted in loss of the splice junction and premature termination at the first tga stop codon of the adjacent intron.
Among unrelated individuals, Argyropoulos et al. (1998) found that heterozygotes for the exon 6 splice donor polymorphism had a 50% reduction in fat oxidation adjusted for lean body mass and a marked elevation in the nonprotein respiratory quotient, compared with wildtype subjects. No significant differences were found between heterozygotes and wildtype individuals for BMI, percentage of body fat, and resting energy expenditure adjusted for lean body mass. The same analyses performed for the V102I polymorphism (602044.0001) showed no significant differences between heterozygotes and wildtype individuals for any of the aforementioned quantitative traits. Nonetheless, the African American population studied had a high prevalence of obesity; therefore, the possibility that this could mask a potential effect of UCP3 mutations on BMI was also examined. Indeed, Argyropoulos et al. (1998) found that the frequency of the g/a heterozygous genotype was nearly twice as high (P = 0.04) in obese (30%) compared with lean (16%) individuals.
Brown et al. (1999) identified a rare mutation in UCP3, arg70-to-trp, in a 15-year-old male of Chinese descent with severe obesity (601665) and type II diabetes (125853). Alignments showed that the mutated valine and arginine residues in V102I (602044.0001) and R70W are completely conserved in all known UCPs, including the plant UCP, suggesting that these residues may play an important functional role. Brown et al. (1999) expressed native human UCP3 mutations in yeast and showed complete loss on the uncoupling activity of UCP3 with R70W and no effect on this activity with V102I.
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