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 car rier that uncouples oxidative ATP phosphorylation. With the capacity t o participate in thermogenesis and energy balance, UCP3 is an importan t obesity candidate gene. A missense polymorphism in exon 3 (V102I) wa s identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the spli ce donor junction of exon 6 were also identified in a compound heteroz ygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and fo und to be similar in Gullah-speaking African Americans and the Mende t ribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-sp lice donor heterozygotes, basal fat oxidation rates were reduced by 50 %, and the respiratory quotient was markedly increased compared with w ild-type individuals, implicating a role for UCP3 in metabolic fuel pa rtitioning.