Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene

Stutzmann, Fanny; Vatin, Vincent; Cauchi, Stéphane; Morandi, Anita; Jouret, Béatrice; Landt, Olfert; Tounian, P.; Lévy-Marchal, Claire; Buzzetti, Raffaella; Pinelli, Leonardo; Balkau, Beverley; Horber, Fritz F.; Bougnères, Pierre; Froguel, Philippe; Meyre, David

doi:10.1093/hmg/ddm132

Cited by 170 publications

(158 citation statements)

References 35 publications

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“…The functional implication of p.V103I in obesity is controversial since several case-control studies found similar 103Ile frequencies between extreme obese and nonobese individuals (Meyre et al, 2009). However, regarding the p.Ile251Leu variant, a meta-analysis conducted by Stutzmann et al (2007) showed a protective effect of the 251Leu allele: individuals carrying this allele have a reduced risk of obesity, nearly 50%, when compared with carriers of the wild-type allele (251Ile). Nevertheless, more studies are necessary to confirm if this polymorphism is or is not associated with BMI.…”

Section: Discussionmentioning

confidence: 99%

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Albuquerque

Estévez

Beato-Víbora

et al. 2014

Annals of Human Genetics

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SummaryWe screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population.A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants.

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Section: Discussionmentioning

confidence: 99%

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Albuquerque

Estévez

Beato-Víbora

et al. 2014

Annals of Human Genetics

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“…These associations were reproducible, using different eating pattern indicators both meaning excessive appetite. Given the effect of MC4R mutations on appetite 30,32,33 the risk of cumulating four false positive associations between MC4R rs17782313 and eating behaviour pattern out of five studies (using five different questionnaires) is unlikely. However our results need to be replicated in additional populations.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation near MC4R is associated with eating behaviour patterns in European populations

et al. 2009

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Both rs17782313 (near MC4R) and rs1421085 (FTO) polymorphisms have been consistently associated with increased risk of obesity and with body mass index (BMI) variation. An effect of both polymorphisms on satiety has recently been suggested. We genotyped rs17782313 and rs1421085 in 5764 relatives from 1109 French pedigrees with familial obesity, 1274 Swiss class III obese adults as well as in 4877 French adults and 5612 Finnish teenagers from two randomly selected population cohorts. In all subjects, eating behaviour traits were documented through questionnaires. We first assessed the association of both single nucleotide polymorphisms with BMI and then studied eating behaviour. Under an additive model, the rs17782313-C MC4R allele showed a trend towards higher percentages of snacking in both French obese children (P ¼ 0.01) and Swiss obese adults (P ¼ 0.04) as well as in adolescents from the Finnish general population (P ¼ 0.04). In French adults with familial obesity, this allele tended to be also associated with a higher Stunkard hunger score (P ¼ 0.02) and in obese children with a higher prevalence of eating large amounts of food (P ¼ 0.04). However, no consistent association of the FTO rs1421085-C allele and available eating behaviour trait was found in our studied populations. The rs17782313-C allele nearby MC4R may modulate eating behaviour-related phenotypes in European obese and randomly selected populations, in both children and adults, supporting a regulatory role of this genetic variant on eating behaviour, as previously shown for MC4R non-synonymous loss-offunction mutations. The potential effect of the obesity-associated FTO gene on eating behaviour deserves additional investigation.

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“…Only one of the 11 non-synonymous mutations (N62S) exhibited a reduced function, as indicated by a strongly reduced cell surface expression, and by signal transduction Table 2 MC4R functional assays MC4R cAMP accumulation and cell surface expression assays. Each amino acid replacement observed in the HGDP-CEPH panel is found in Table. Three sites (R7C, V103I, I251L) were not functionally tested in this study as these sites have been identiWed and assayed previously (Srinivasan et al 2004;Stutzmann et al 2007;Xiang et al 2006). Construct properties that did not result in an enhancement of intracellular cAMP levels (Table 2).…”

Section: Functional Characterization Of Non-synonymous Mutationsmentioning

confidence: 99%

Increased constraints on MC4R during primate and human evolution

et al. 2008

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The melanocortin 4 receptor (MC4R) is routinely investigated for the role it plays in human obesity, as mutations in MC4R are the most common dominantly inherited form of the disease. As little is known about the evolutionary history of this locus, we investigated patterns of variation at MC4R in a worldwide sample of 1,015 humans from 51 populations, and in 8 central chimpanzees. There is a signiWcant paucity of diversity at MC4R in humans, but not in chimpanzees. The spectrum of mutations in humans, combined with the overall low level of diversity, suggests that most (if not all) of the observed non-synonymous polymorphisms are likely to be transient deleterious mutations. The MC4R coding region was resequenced in 12 primate species and sequences from an additional 29 vertebrates were included in molecular evolutionary analyses. MC4R is highly conserved throughout vertebrate evolution, and has apparently been subject to high levels of continuous purifying selection that increased approximately threefold during primate evolution. Furthermore, the strong selection extends to codon usage bias, where most silent mutations are expected to be either quickly Wxed or removed from the population, which may help explain the unusually low levels of silent polymorphisms in humans. Finally, there is a signiWcant tendency for non-synonymous mutations that impact MC4R function to occur preferentially at sites that are identiWed by evolutionary analyses as being subject to very strong purifying selection. The information from this study should help inform future epidemiological investigations of MC4R.

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Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene

Cited by 170 publications

References 35 publications

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Common genetic variation near MC4R is associated with eating behaviour patterns in European populations

Increased constraints on MC4R during primate and human evolution

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