Novel melanocortin 4 receptor gene mutations in severely obese children

• Published in: Clinical endocrinology (Oxford) Vol. 68; no. 4; pp. 529 - 535
• Main Authors: Lee, Yung Seng, Poh, Larry Kok Seng, Kek, Betty Lay Kee, Loke, Kah Yin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2008; Blackwell
• Subjects: Biological and medical sciences; Case-Control Studies; Child; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetic Testing; Humans; Male; Medical sciences; Metabolic diseases; Mutation; Obesity; Obesity - genetics; Phenotype; Receptor, Melanocortin, Type 4 - genetics; Severity of Illness Index; Singapore; Vertebrates: endocrinology; Singapore; Human; Obesity; Gene; Nutrition disorder; Genetics; Mutation; Child; Endocrinology; Nutritional status; Melanocortin receptor
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2007.03071.x

Summary
Objective  Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children.
Design  We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing.
Results  We identified three mutations in three subjects: 4 bp deletion from nucleotides 631–634 (c.631–634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1·32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non‐obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early‐onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity.
Conclusion  MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.