Mutations in the melanocortin 4 receptor gene (MC4R) are the most common cause of monogenic human obesity. As part of our ongoing project entitled 'Turkish Obesity Genome Study' we determined the nucleotide sequence of the entire coding region of the MC4R gene in 40 morbidly obese subjects from independent families. Here we report a novel heterozygous mutation (N274S) in an adult female obese individual (age: 52 yrs, BMI 41.7 kg/m(2), height 158 cm, weight: 104 Kg). The sister of the index case (age: 55 yrs, height: 160 cm, weight: 110 Kg, BMI: 43 kg/m(2)) also carries the same mutation. Although both sisters were morbidly obese and hypertensive the index case had normal plasma insulin and fasting blood glucose levels whereas her sister had type 2 diabetes mellitus. No abnormalities of the reproductive function were present. Despite marked hyperphagia in childhood both sisters had a history of relatively diminished intensity of appetite after the age of 20. Of notice, index case was diagnosed to have cyclothymia whereas her sister was being treated for bipolar affective disorder. Detailed clinical evaluation revealed normal bone mineral density and serum calcium parameters as well as intact thyroid axis and hypothalamus-pituitary-adrenal axis in both patients. The human MC4-R deficient phenotype resembles the murine deficient state with regard to preserved reproductive function although hyperphagia, increased linear growth and absence of diabetes in mice are not observed in humans. Affected individuals have hyperphagia in childhood, which looses intensity later in life, and they also present with normal height and diabetes mellitus. Accumulating evidence indicate that melanocortin endocrine system or defective melanocortin signaling has inherently different characteristics in mice and humans resembling the variation observed with regard to leptin deficiency in both species.