A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity

Mutations in the melanocortin 4 receptor gene (MC4R) are the most common ca use of monogenic human obesity. As part of our ongoing project entitled 'Tu rkish Obesity Genome Study' we determined the nucleotide sequence of the en tire coding region of the MC4R gene in 40 morbidly obese subjects from inde pendent families. Here we report a novel heterozygous mutation (N274S) in a n 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: 16 0 cm, weight: 110 Kg, BMI: 43 kg/m(2)) also carries the same mutation. Alth ough both sisters were morbidly obese and hypertensive the index case had n ormal plasma insulin and fasting blood glucose levels whereas her sister ha d type 2 diabetes mellitus. No abnormalities of the reproductive function w ere present Despite marked hyperphagia in childhood both sisters had a hist ory 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 pati ents. The human MC4-R deficient phenotype resembles the murine deficient st ate with regard to preserved reproductive function although hyperphagia, in creased linear growth and absence of diabetes in mice are not observed in h umans. Affected individuals have hyperphagia in childhood, which looses int ensity later in life, and they also present with normal height and diabetes mellitus. Accumulating evidence indicate that melanocortin endocrine syste m or defective melanocortin signaling has inherently different characterist ics in mice and humans resembling the variation observed with regard to lep tin deficiency in both species.