A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity

• Published in: The journal of clinical endocrinology and metabolism Vol. 87; no. 3; pp. 1423 - 1426
• Main Authors: LEE, Yung-Seng, POH, Larry Kok-Seng, LOKE, Kah-Yin
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.03.2002
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; Child, Preschool; Endocrinopathies; Female; General aspects. Associated endocrine diseases. Endocrine paraneoplasic syndromes; Genotype; Heterozygote; Humans; Infant; Male; Medical sciences; Metabolic diseases; Mutation - physiology; Obesity; Obesity - genetics; Obesity, Morbid - genetics; Pedigree; Receptor, Melanocortin, Type 3; Receptors, Corticotropin - genetics; Human; Obesity; Rodentia; Nutrition disorder; Melanocyte stimulating hormone; Weight; Heterozygosity; Polymerase chain reaction; Vertebrata; Regulation(control); Mammalia; Gene; Mouse; Animal; Models; Mutation; Severe; Father; Child; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.87.3.1423

The melanocortin 3 receptor (MC3R) plays a critical role in weight regulation as demonstrated in mouse models. We describe a novel mutation Ile183Asn (T548A) found in heterozygosity in a 13-year-old obese girl and her father. The MC3R gene was sequenced in 41 unrelated obese children, and 121 DNA samples from non-obese individuals were analysed for this novel sequence variant by allele-specific polymerase chain reaction (PCR). The genotypes of four family members of the pedigree were also analysed by allele-specific PCR. Ile183Asn was found in the proband and her father, though all four family members were obese. The sequence variant was not found in 121 control samples. The proband has high percentage body fat (49%), but the father's percentage body fat was only 30%. There were no distinguishing phenotypic features. Insulin sensitivity was significantly higher compared to the 40 other obese subjects without MC3R gene mutations. The difference in phenotypes between the two related heterozygotes, and the observation of obesity in other family members without the mutation suggests that obesity results from a varying combination of environmental, behavioural and multiple genetic factors (other than MC3R), even within the same family.