Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes

J Clin Invest. 1998 Oct 1;102(7):1345-51. doi: 10.1172/JCI4115.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • African Continental Ancestry Group / genetics
  • Alternative Splicing
  • Base Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Codon, Terminator
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Energy Metabolism / genetics
  • Ethnic Groups
  • European Continental Ancestry Group / genetics
  • Exons
  • Female
  • Genetic Carrier Screening
  • Humans
  • Ion Channels
  • Lipolysis / genetics*
  • Male
  • Mitochondrial Proteins
  • Models, Molecular
  • Obesity*
  • Oxygen Consumption / genetics
  • Pedigree
  • Point Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Protein Conformation
  • Sierra Leone
  • Uncoupling Protein 3

Substances

  • Carrier Proteins
  • Codon, Terminator
  • Ion Channels
  • Mitochondrial Proteins
  • UCP3 protein, human
  • Uncoupling Protein 3