Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.
Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that 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 wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.
Department of Medicine, Division of Endocrinology, Medical University of South Carolina, 29425, USA. argyrog@musc.edu
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Argyropoulos
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Brown
S M
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Willi
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Zhu
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Reitman
S M
SM
Gevao
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I
Spruill
W T
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Garvey
D017398:Alternative Splicing; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D018388:Codon, Terminator; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D005006:Ethnicity; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D007473:Ion Channels; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D024101:Mitochondrial Proteins; D008958:Models, Molecular; D009765:Obesity; D010101:Oxygen Consumption / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D012807:Sierra Leone; D000071247:Uncoupling Protein 3; D044465:White People / Q000235:genetics; D001741:Black or African American
D002352:Carrier Proteins; D018388:Codon, Terminator; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3