A leptin missense mutation associated with hypogonadism and morbid obesity

Mutations in the mouse leptin gene lead to severe obesity. Leptin-deficient ob/ob mice exhibit a complex phenotype which includes infertility, hypothermia and cold intolerance, hypercortisolemia and other endocrine and metabolic abnormalities. In humans, obesity is generally not associated with leptin deficiency, and a positive correlation exists between body mass index (BMI) and serum leptin levels. Such a correlation was also found in a Turkish population of 203 obese and non-obese patients. One individual, however, with a BMI of 55.8 kg/m super(2) had very low serum leptin concentrations (0.9 ng/ml). A C arrow right T substitution was identified in codon 105 of the leptin gene (LEP) of this individual (patient 24), resulting in an Arg arrow right Trp replacement in the mature protein. The C arrow right T substitution abolishes an MspI restriction site, allowing rapid PCR-screening for the mutation in members of the patient's family. Two other individuals (14 and 31) were homozygous for the mutation, markedly obese and had low levels of serum leptin with regard to their elevated BMI. All three homozygotes were markedly hyperphagic. Their plasma-insulin concentrations were elevated, and patient 14 was hyperglycaemic. All other members of the family were either heterozygous for the mutation or homozygous for the wild-type allele and had normal body weight, serum leptin levels, fasting blood glucose and plasma insulin levels, indicating a recessive mutation responsible for a monogenic obesity.