Identification of a Rare and Potential Pathogenic MC4R Variant in a Brazilian Patient With Adulthood-Onset Severe Obesity

Abstract

BackgroundThe melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity.MethodsThis study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0–11 years), 19 patients in the adolescence/youth-onset group (12–21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject’s DNA was assessed using automated Sanger sequencing.ResultsSignificant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity.ConclusionThis study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants

“…MC4R is a member of the melanocortin receptor family and is involved in energy balance by interacting with melanocyte stimulating hormone ( 33 ). Genetic defects in MC4R cause obesity ( 34 ).…”

Association between genetic variants in ANGPTL4 (T266M) and MC4R genes predisposing to obesity

“…In the hypothalamus, the paraventricular nucleus is where the satiety-and energy expenditure-inducing peptides -MSH, cocaine and amphetamine-regulated transcript (CART), and other related peptides bind to MC4R during meal intake. On other hand, the MC4R antagonist neuropeptide AgRP (agouti-related peptide) promotes both an increase in hunger and a decrease in energy expenditure in a low energy state (27). This is the first study undertaken to examine the role of MC4R rs13447324 in causing obesity in Iraq.…”

A Inteligência Artificial E Suas Implicações No Campo Da Genética

“…Todas as variantes foram rastreadas em probandos com obesidade grave e candidatos a cirurgia bariátrica pelo SUS (FONSECA et al, 2019;SALUM et al, 2020).…”

“…Ainda hoje, um dos grandes desafios da ciência e medicina é identificar os pacientes com obesidade monogênica não sindrômica (OMNS) dentro do grupo caracterizado como poligênico. Essa dificuldade pode ser explicada pela falta de conhecimento sobre essa forma genética e também por poucos estudos focados no diagnóstico e na caracterização desse grupo, o que possibilitaria identificar biomarcadores para a doença (DA FONSECA; BOZZA; CABELLO, 2020;SALUM et al, 2020SALUM et al, , 2021. Neste contexto, o presente capítulo visa realizar uma revisão sobre o tema, trazendo as principais formas e os tratamentos disponíveis.…”