EVIDENCE THAT THE DIABETES GENE ENCODES THE LEPTIN RECEPTOR - IDENTIFICATION OF A MUTATION IN THE LEPTIN RECEPTOR GENE IN DB DB MICE/

OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternative ly spliced transcript that encodes a form of mouse OB-R with a long in tracellular domain, db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates t he intracellular domain. We further identified a G-->T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon reta ined in the OB-R transcript. We predict that the long intracellular do main form of OB-R is crucial for initiating intracellular signal trans duction, and as a corollary, the inability to produce this form of OB- R leads to the severe obese phenotype found in db/db mice.