The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity.

T he Lepr/Lepr mouse is an autosomal recessive model of extreme obesity that phenotypically appears very similar to the Lepr/Lepr mouse, in which the leptin protein is absent (1). However, in the Lepr/Lepr mouse, the leptin protein is structurally normal (1). Leptin is ineffectual when injected into Lepr/Lepr mice, indicating that they are resistant to the action of this hormone (1). Recently, Lee et al. (2) and Chen et al. (3) demonstrated a point mutation in the leptin receptor of the Lepr/Lepr mouse that results in abnormal splicing of leptin receptor mRNA. Furthermore, studies of the leptin receptor in the Zucker fatty rat and the Koletsky rat have found mutations in the leptin receptor that also associate with extreme obesity (4,5). Although the leptin receptor has been identified in humans, its potential role in the development of obesity is still under investigation. In Pima Indians, a marker near the leptin receptor on chromosome 1 has been linked to acute insulin release (6). Considine et al. (7) studied leptin receptor cDNA in seven lean and eight obese subjects and found an adenosine-to-guanine substitution at nucleotide 861 that predicts a nonconservative substitution of glutamine to arginine at amino acid 223 (Gln^Arg) in the extracellular domain of the receptor. This amino acid substitution is at a site near the pathogenic mutation in the leptin receptor of the Zucker fatty rat, suggesting that this substitution may be clinically relevant. However, the GlnArg substitution did not associate with the obese phenotype in this small number of subjects (7). Additionally, in exon 12, a guanine-to-cytosine substitution was found at