Prevalence of rare MC3R variants in obese cases and lean controls

Abstract

The role of mutations in the melanocortin-3 receptor (MC3R) gene, which is implicated in the regulation of energy homeostasis, is still under debate. Animal studies have clearly proven that, together with the melanocortin-4 receptor (MC4R), the MC3R is a critical receptor for melanocortin peptides within the leptin-melanocortin signaling cascade. However, as several mutations have been found in lean individuals and not all mutations seem to cause receptor dysfunction, results from mutation screens in obese humans remain controversial. In the present study, we screened for rare variants in the MC3R gene of obese children and lean controls to assess the prevalence of MC3R mutations in the Belgian population. We screened 249 severely overweight and obese children and adolescents and 239 lean adults for mutations in the coding region of MC3R. Mutation screening was performed by high resolution melting curve analysis and direct sequencing. We identified four non-synonymous coding variations in the obese population, all of which had been reported previously. In addition, we also found four novel rare MC3R variants in the lean control population, suggesting that not all MC3R mutations are disease-causing. Overall, the total prevalence of rare MC3R variants was 1 % in Belgian obese children and adolescents compared to 1.02 % in lean controls. Ultimately, cosegregation studies combined with comprehensive functional analysis is required to determine the potential pathogenic role of rare MC3R variants in causing human obesity.

Loss‐of‐function mutations in the melanocortin‐3 receptor gene confer risk for human obesity: A systematic review and meta‐analysis

“…Consequently, 68 references were selected for full‐text review, of which 62 were excluded for one or more of the following reasons: (a) inappropriate population, (b) ineligible MC3R genetic variant (eg, common variants), (c) inadequate study design, (d) full text not available, (e) same data published/presented in multiple journals/meetings/conferences/theses, and (f) absence of comparator group (Figure ). A total of six independent studies were considered eligible for the meta‐analysis.…”

“…In contrast, Lee et al only screened the entire coding region of MC3R in cases with obesity and genotyped the identified mutations in controls with normal weight to determine the prevalence of those mutations. Two studies included participants with overweight and obesity, the other two independent studies recruited individuals with obesity, and the remaining two independent studies focused on participants with severe obesity …”

“…(Figure 1). A total of six independent studies [24][25][26][27][28][40][41][42] were considered eligible for the meta-analysis. Table 1 describes the characteristics of the included studies.…”

“…21,22 So far, at least 33 rare coding mutations in MC3R have been identified and classified as either pathological, benign, or of unclear effect 23 ; however, attempts to link these coding mutations with human obesity have been inconsistent. [24][25][26][27][28] Possible explanations for these discrepancies include insufficient statistical power; lack of proper functional characterization of mutations; incomplete penetrance of the mutations, gene-gene, gene-environment, gene-age, or gene-sex interactions; and genetic heterogeneity. 29,30 Systematic reviews of the literature, followed by meta-analyses, have proven to be a powerful strategy in conclusively demonstrating the association of common polymorphisms with polygenic obesity.…”

Design of cyclized selective melanotropins

“…The major functions of MC2R include the production of glucocorticoids as well as the fear/flight response . MC3R is expressed in the brain, placenta, gut, heart, septum, hippocampus, and the thalamus . MC3R is involved in obesity, regulation of energy (homeostasis), inflammation, as well as sexuality .…”