AMINO-ACID VARIANTS IN THE HUMAN LEPTIN RECEPTOR - LACK OF ASSOCIATION TO JUVENILE-ONSET OBESITY

The recently described putative lipostat system mediated in part by le ptin and its hypothalamic receptor provides logical candidate genes fo r the molecular basis of inherited obesity in humans on the basis of t he occurrence of profound obesity observed in obese and diabetic mice, in which the genes for leptin or its receptor, respectively, are muta ted. In this study we tested the hypothesis that juvenile onset obesit y in humans may be caused by leptin resistance mediated through geneti c variations in isoforms of the hypothalamic leptin receptor. One hund red and fifty-six obese Danish men with a history of juvenile onset ob esity were selected at the draft board examination with a body mass in dex (BMI) greater than or equal to 31 kg/m(2). From the same study pop ulation a control group of 205 control subjects (mean BMI = 21,5 kg/m( 2)) were randomly selected. Single strand conformational polymorphism scanning of genomic DNA from 56 obese subjects revealed a total of fou r amino acid variants located in coding exons 2, (Lys109Arg), 4 (Lys20 4Arg and Gln223Arg), and 12 (Lys656Asn), respectively. The codons 109, 223, and 656 variants were common, but their prevalence was not signi ficantly different between obese and lean carriers with regard to alle le or carrier frequency (p > 0.1 in each case). The codon 204 mutation was only found in one obese subject. In conclusion, it is unlikely th at mutations in the coding region of the long isoform of the leptin re ceptor are a common cause of juvenile onset obesity. (C) 1997 Academic Press.