THE HUMAN UNCOUPLING PROTEIN-3 GENE - GENOMIC STRUCTURE, CHROMOSOMAL LOCALIZATION, AND GENETIC-BASIS FOR SHORT AND LONG FORM TRANSCRIPTS

Uncoupling protein-3 (UCP3) is a recently identified candidate mediato r of adaptive thermogenesis in humans. Unlike UCP1 and UCP2, UCP3 is e xpressed preferentially and at high levels in human skeletal muscle an d exists as short and long form transcripts, UCP3(S) and UCP3(L). UCP3 (S) is predicted to encode a protein which lacks the last 37 C-termina l residues of UCP3(L). In the present study, we have defined the intro n-exon structure for the human UCP3 gene and determined that UCP3(S) i s generated when a cleavage and polyadenylation signal (AATAAA) locate d in the last intron prematurely terminates message elongation. In add ition we have mapped UCP3 to the distal segment of human chromosome 11 q13 (between framework markers D11S916 and D11S911), adjacent to UCP2. Of note, UCP2 and UCP3 in both mice and humans colocalize in P1 and B AC genomic clones indicating that these two UCPs are located within 75 -150 kilobases of each other and most likely resulted from a gene dupl ication event. Previous studies have noted that mouse UCP2 maps to a r egion of chromosome 7 which is coincident with three independently map ped quantitative trait loci for obesity. Our study shows that UCP3 is also coincident with these quantitative trait loci raising the possibi lity that abnormalities in UCP3 are responsible for obesity in these m odels.