Prevalence, Spectrum, and Functional Characterization of Melanocortin-4 Receptor Gene Mutations in a Representative Population-Based Sample and Obese Adults from Germany

Hinney, Anke; Bettecken, Thomas; Tarnow, Patrick; Brumm, Harald; Reichwald, Kathrin; Lichtner, Peter; Scherag, André; Nguyen, Thuy Trang; Schlumberger, Pia; Rief, Winfried; Vollmert, Caren; Illig, Thomas; Wichmann, H‐Erich; Schäfer, Helmut; Platzer, Matthias; Biebermann, Heike; Meitinger, Thomas; Hebebrand, Johannes

doi:10.1210/jc.2005-2056

Cited by 181 publications

(167 citation statements)

References 44 publications

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“…To date about 90 such mutations have been identiWed and functionality determined by an in vitro cAMP accumulation assay. A quantitative eVect of MC4R mutations on body mass index (BMI) has also been observed (DempXe et al 2004); individuals who are homozygotes or compound heterozygotes for MC4R mutations (non-synonymous, frameshift or premature stop mutations) are more obese than individuals who are heterozygous for the same allele (Hinney et al 2006), consistent with observations in Mc4r knockout mice. However, it is not uncommon for heterozygous relatives of obese probands to not exhibit early onset obesity (DempXe et al 2004).…”

Section: Introductionsupporting

confidence: 59%

“…In addition to humans and chimpanzees we also sequenced MC4R from 10 other primate species, and analyzed the molecular evolution of MC4R in a total of 41 vertebrate species, to determine the mode of evolution (purifying, neutral or adaptive) that has been acting on MC4R across 420 million years of vertebrate evolution, as well as to determine if the pattern of evolution has changed on any particular lineage during this time. Given previous observations of human MC4R variation (Hinney et al 2006) and GPCR conservation ), we hypothesize that MC4R has been largely subject to purifying selection throughout vertebrate evolution, and that MC4R variants in human populations will be rare, deleterious, de novo mutations.…”

Section: Introductionmentioning

confidence: 77%

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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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Section: Introductionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 77%

Increased constraints on MC4R during primate and human evolution

et al. 2008

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“…It is thought to explain 2-6% of extremely obese childhood and adolescent cases (Farooqi et al, 2003;Hinney et al, 2003Hinney et al, , 2006Santini et al, 2004;Wang & Tao, 2011). The MC4R is a membrane-bound G-protein-coupled receptor that activates adenylate cyclase; in response to the α-melanocyte-stimulating hormone (α-MSH), MC4R induces production of cAMP (Stutzmann et al, 2008;Caruso et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Various missense, nonsense and frameshift MC4R mutations have been described (Human Mutation Database, HGMD; http://www.hgmd.cf.ac.uk) in a wide patient series with distinct ancestral origins. Currently, the clinical genotype-phenotype relationships in adult MC4R mutation carriers constitute an essential objective to define and corroborate the severity of each functional alteration (Hinney et al, 2003(Hinney et al, , 2006Lubrano-Berthelier et al, 2006;Wang & Tao, 2011). To date, more than 150 different MC4R mutations, mostly leading to a reduced function, have been detected in obese individuals (Hinney et al, 2013).…”

Section: Introductionmentioning

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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“…Evidence is accumulating that most of these genes encoding central peptide factors as well as their receptors (leptin receptors, melanocortin receptors, NPY receptors) are polymorphic. Dominant inheritance of obesity conferred by missense, nonsense and frameshift mutations in the melanocortin 4 receptor (MC4R) gene has been extensively reported in many populations including French, English, German, American, Italian and Spanish individuals 2,[7][8][9][10] . It has been estimated that 1-6% of extremely obese individuals harbour functionally relevant MC4R mutations.…”

Section: Genetics Of Body Weight Regulationmentioning

confidence: 99%

Genetics of obesity

Martínez-Hernández

Enríquez²,

Moreno-Moreno

et al. 2007

Public Health Nutr.

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Objective: The aim was to review and update advances in genetics of obesity. Design: Analysis and interpretation of recent investigations about regulating the energy balance as well as about gene-nutrient interactions and current nutrigenomic research methods. Background and main statements: Obesity results from a long-term positive energy balance. However, its rising prevalence in developed and developing societies must reflect lifestyle changes, since genetic susceptibility remains stable over many generations. Like most complex diseases, obesity derives from a failure of adequate homoeostasis within the physiological system controlling body weight. The identification of genes that are involved in syndromic, monogenic and polygenic obesity has seriously improved our knowledge of body weight regulation. This disorder may arise from a deregulation at the genetic level (e.g. gene transcription or altered protein function) or environmental exposure (e.g. diet, physical activity, etc.). Conclusions: In practice, obesity involves the interaction between genetic and environmental factors.

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Prevalence, Spectrum, and Functional Characterization of Melanocortin-4 Receptor Gene Mutations in a Representative Population-Based Sample and Obese Adults from Germany

Cited by 181 publications

References 44 publications

Increased constraints on MC4R during primate and human evolution

Increased constraints on MC4R during primate and human evolution

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

Genetics of obesity

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