Spontaneous mutation in the db gene results in obesity and diabetes in CD-1 outbred mice

Five allelic mutants of the diabetes (db) gene have been previously describ ed in mice and rats causing obesity, infertility, and varying degrees of di abetes. We have identified a new, spontaneous mutation resulting in obesity and diabetes in a colony of CD-1 outbred mice, Mus musculus domesticus. Ge netic complementation studies indicated that the new mutation was an allele of the diabetes locus. Sequence analysis of cDNA fragments showed a deleti on of one G residue located in exon 12 of the leptin receptor gene. The mut ation, Lepr(db-NCSU), results in a frameshift and reduces Lepr transcript l evels 10-fold. Mutant mice drank up to four times more water and were up to two times heavier than wild-type mice. Blood glucose and plasma insulin an d leptin concentrations were sexually dimorphic among affected mice, sugges ting an effect of sex steroids. Mortality of affected males was 100% by 5 m o, whereas affected females survived up to 10 mo of age.