Salum Kaio Cezar Rodrigues, de Souza Guilherme Orofino, Abreu Gabriella de Medeiros, Campos Junior Mário, Kohlrausch Fabiana Barzotto, Carneiro João Regis Ivar, Nogueira Neto José Firmino, Magno Fernanda Cristina C Mattos, Rosado Eliane Lopes, Palhinha Lohanna, Maya-Monteiro Clarissa Menezes, de Cabello Giselda Maria Kalil, Cabello Pedro Hernán, Bozza Patrícia Torres, Zembrzuski Verônica Marques, da Fonseca Ana Carolina Proença
Human Genetic Laboratory, Department of General Biology, Institute of Biology, Federal Fluminense University, Niterói, Brazil.
Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Front Genet. 2020 Dec 9;11:608840. doi: 10.3389/fgene.2020.608840. eCollection 2020.
The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the () 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 gene in a Brazilian cohort of adults with severe obesity.
This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m, 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 coding region of each subject's DNA was assessed using automated Sanger sequencing.
Significant 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.
This 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 variant in a Brazilian patient with severe and adulthood-onset obesity.
黑皮质素能途径调节能量平衡，该系统受损常导致体重增加。已描述了（）基因中的罕见变异导致功能部分或完全丧失，呈常染色体共显性遗传。这些突变是非综合征性单基因肥胖的最常见原因。在此背景下，本研究旨在对巴西一组严重肥胖成年人的该基因进行测序。
本研究纳入了163名体重指数（BMI）≥35 kg/m²的无亲缘关系的先证者，根据肥胖发病时间分为三组。在总样本中，25例患者纳入儿童期发病组（0 - 11岁），19例患者纳入青少年/青年期发病组（12 - 21岁），119例患者纳入成年期发病组（>21岁）。获取血压、人体测量和生化特征，并使用自动桑格测序法评估每个受试者DNA的编码区。
观察到各组之间存在显著的人体测量差异。与成年期发病肥胖组相比，儿童期发病或青少年/青年期发病的患者体重和BMI中位数更高。共鉴定出五个突变，包括四个错义变体：p.Ser36Thr、p.Val103Ile、p.Ala175Thr和p.Ile251Leu。此外，我们观察到一个同义变体（p.Ile198=）。p.Ala175Thr变体在一名严重肥胖且成年期发病的女性病例中被鉴定出来。该变体先前被描述为功能部分丧失突变，其中次要等位基因具有显性负效应，可能导致cAMP活性降低。
本研究显示在一组严重肥胖且符合减肥手术条件的巴西成年人队列中存在常见和罕见变体。我们在一名严重肥胖且成年期发病的巴西患者中鉴定出一种罕见的潜在致病变体。
