title: Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr).
abstract: The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that fa and diabetes (db) are homologous loci in the rat and mouse genomes, respectively. It has been shown that db alleles carry mutations in the Lepr (leptin receptor) gene. This paper describes a point mutation in the fatty allele of Lepr. A nucleotide substitution at position 880 (A-->C) causes an amino acid substitution at position 269 (Gln-->Pro). The mutation generates a novel Msp I site that cosegregates with fa in 1,028 meioses examined in obese F2 progeny from two crosses (Bnx13M and WKYx13M) and is still segregating in three rat colonies. PCR-based mutagenesis was used to introduce the fa mutation into the mouse Lepr cDNA. Transient transfection studies indicate that the mutant Lepr cDNA has greatly reduced binding of leptin (Lep) at the cell surface. These data are strong evidence that the single nucleotide substitution in the fa allele of Lepr (Leprfa) is responsible for the obese phenotype.
authors.affiliation: Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, NY 10021, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chua
authors.forename: D W
authors.initials: DW
authors.lastname: White
authors.forename: X S
authors.initials: XS
authors.lastname: Wu-Peng
authors.forename: S M
authors.initials: SM
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Okada
authors.forename: E E
authors.initials: EE
authors.lastname: Kershaw
authors.forename: W K
authors.initials: WK
authors.lastname: Chung
authors.forename: L
authors.initials: L
authors.lastname: Power-Kehoe
authors.forename: M
authors.initials: M
authors.lastname: Chua
authors.forename: L A
authors.initials: LA
authors.lastname: Tartaglia
authors.forename: R L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D020738:Leptin; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine / Q000378:metabolism*; D054411:Receptors, Leptin
chemical_list: D002352:Carrier Proteins; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D054411:Receptors, Leptin; C515447:leptin receptor, mouse