Identification of the MC4R start lost mutation in a morbidly obese Brazilian patient

Abstract

Ana Carolina Proença da Fonseca,1 Gabriella de Medeiros Abreu,1 Verônica Marques Zembrzuski,1 Mario Campos Junior,1 João Regis Ivar Carneiro,2 Fernanda Cristina C Mattos Magno,3 Eliane Lopes Rosado,3 José Firmino Nogueira Neto,4 Giselda Maria Kalil de Cabello,1 Pedro Hernán Cabello1,5 1Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil; 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Institute of Nutrition Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 4Department of Pathology and Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil; 5Human Genetics Laboratory, Grande Rio University, Rio de Janeiro, Brazil Background: Melanocortin 4 receptor gene (MC4R) is an important regulator of food intake, body weight, and blood pressure. Mutations in MC4R are associated with the most common form of nonsyndromic monogenic obesity. MC4R variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding MC4R variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the MC4R gene in a Brazilian cohort of severely obese adults and to investigate the phenotype–genotype correlation within MC4R variant carriers. Methods: This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0–11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12–21 years). The entire coding region of MC4R gene was screened by Sanger sequencing. Results: As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of MC4R. It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with MC4R missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying MC4R variants had higher median of waist–hip ratio when compared to noncarriers (P=0.048). These missense variants were also associated with hypertension (P=0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers (P=0.020 and P=0.065, respectively). Val103Ile was also associated with hypertension (P=0.003). Conclusion: This study showed the prevalence of MC4R variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of MC4R on body fat distribution and blood pressure. Keywords: MC4R, severe obesity, mutation, start lost, blood pressure

Keywords

• MC4R
• Morbid Obesity
• Mutation
• Start lost
• Blood pressure-;