Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr)

Streamson C. Chua, Jr., David W. White, X. Sharon Wu-Peng, Shun Mei Liu, Norichika Okada, Erin E. Kershaw, Wendy K. Chung, Loraine Power-Kehoe, Melvin Chua, Louis A. Tartaglia, Rudolph L. Leibel

Research output: Contribution to journalArticle

256 Citations (Scopus)

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 (Lepr(fa)) is responsible for the obese phenotype.

Original languageEnglish (US)
Pages (from-to)1141-1143
Number of pages3
JournalDiabetes
Volume45
Issue number8
StatePublished - 1996
Externally publishedYes

Fingerprint

Leptin Receptors
Phenotype
Mutation
Alleles
Nucleotides
Complementary DNA
Hyperphagia
Thermogenesis
Meiosis
Amino Acid Substitution
Leptin
Point Mutation
Mutagenesis
Transfection
Adipose Tissue
Obesity
Genome
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Chua, Jr., S. C., White, D. W., Wu-Peng, X. S., Liu, S. M., Okada, N., Kershaw, E. E., ... Leibel, R. L. (1996). Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). Diabetes, 45(8), 1141-1143.

Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). / Chua, Jr., Streamson C.; White, David W.; Wu-Peng, X. Sharon; Liu, Shun Mei; Okada, Norichika; Kershaw, Erin E.; Chung, Wendy K.; Power-Kehoe, Loraine; Chua, Melvin; Tartaglia, Louis A.; Leibel, Rudolph L.

In: Diabetes, Vol. 45, No. 8, 1996, p. 1141-1143.

Research output: Contribution to journalArticle

Chua, Jr., SC, White, DW, Wu-Peng, XS, Liu, SM, Okada, N, Kershaw, EE, Chung, WK, Power-Kehoe, L, Chua, M, Tartaglia, LA & Leibel, RL 1996, 'Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr)', Diabetes, vol. 45, no. 8, pp. 1141-1143.
Chua, Jr. SC, White DW, Wu-Peng XS, Liu SM, Okada N, Kershaw EE et al. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). Diabetes. 1996;45(8):1141-1143.
Chua, Jr., Streamson C. ; White, David W. ; Wu-Peng, X. Sharon ; Liu, Shun Mei ; Okada, Norichika ; Kershaw, Erin E. ; Chung, Wendy K. ; Power-Kehoe, Loraine ; Chua, Melvin ; Tartaglia, Louis A. ; Leibel, Rudolph L. / Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). In: Diabetes. 1996 ; Vol. 45, No. 8. pp. 1141-1143.
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AU - Liu, Shun Mei

AU - Okada, Norichika

AU - Kershaw, Erin E.

AU - Chung, Wendy K.

AU - Power-Kehoe, Loraine

AU - Chua, Melvin

AU - Tartaglia, Louis A.

AU - Leibel, Rudolph L.

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N2 - 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 (Lepr(fa)) is responsible for the obese phenotype.

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