The cloning of leptin and its receptor have led to the identification of a novel signal transduction pathway important in body weight regulation (Zhang et al. 1994; Tartaglia et al. 1995; Lee et al. 1996). Previous data have indicated that the db gene encodes several alternatively spliced forms of the receptor for the ob gene product, leptin (Tartaglia et al. 1995; Lee et al. 1996; Chen et al. 1996). Of these splice forms, only one, Ob-Rb, contains a long cytoplasmic domain, which includes motifs implicated in signal transduction. Ob-Rb is highly expressed in the hypothalamus and is abnormally spliced in C57BL/Ks db/db mice. This mutation results in the truncation of the Ob-Rb splice form and loss of its signal transducing capability (Lee et al. 1996; Ghilardi et al. 1996; Vaisse et al. 1996). Recently a missense mutation in Lepr was identified in the fatty (fa/fa) Zucker rat (Chua et al. 1996). This mutation presumably alters the binding of leptin at the cell surface (Chua et al. 1996; Philips et al. 1996). Mutations in the mouse db locus and its rat homolog, fatty, have independently arisen many times (Hummel et al. 1966; Aubert et al. 1985; Koletsky 1973; Leiter et al. 1980; Truett et al. 1991). The molecular basis of the mutations in these other mutant strains could provide information on the structure-function relationship of leptin and Lepr. Here we report the molecular basis of the mutations in the coding regions of Lepr from mutant 129 db3J/db 3J rats and NIH faCP/fa cp rats.