Chua S C, White D W, Wu-Peng X S, Liu S M, Okada N, Kershaw E E, Chung W K, Power-Kehoe L, Chua M, Tartaglia L A, Leibel R L
Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, NY 10021, USA.
Diabetes. 1996 Aug;45(8):1141-3. doi: 10.2337/diab.45.8.1141.
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.
大鼠脂肪（fa）突变会导致早发性严重肥胖，其原因是食欲亢进、非寒战产热缺陷以及能量优先沉积于脂肪组织。基因定位研究表明，fa和糖尿病（db）分别是大鼠和小鼠基因组中的同源位点。已证明db等位基因在Lepr（瘦素受体）基因中携带突变。本文描述了Lepr脂肪等位基因中的一个点突变。第880位核苷酸的替换（A→C）导致第269位氨基酸的替换（Gln→Pro）。该突变产生了一个新的Msp I位点，在来自两个杂交组合（Bnx13M和WKYx13M）的肥胖F2后代中检测的1028次减数分裂中，该位点与fa共分离，并且仍在三个大鼠群体中分离。基于PCR的诱变被用于将fa突变引入小鼠Lepr cDNA。瞬时转染研究表明，突变的Lepr cDNA在细胞表面对瘦素（Lep）的结合能力大大降低。这些数据有力地证明，Lepr（Leprfa）的脂肪等位基因中的单核苷酸替换是肥胖表型的原因。
