Melanocortin-4 Receptor Gene Mutations in a Group of Turkish Obese Children and Adolescents

Tunç, Selma; Demir, Korcan; Tükün, Fatma Ajlan; Topal, Cihan; Hazan, Fılız; Saglam, Burcu; Nalbantoğlu, Özlem; Yildiz, Melek; Özkan, Behzat

doi:10.4274/jcrpe.4225

Cited by 14 publications

(11 citation statements)

References 22 publications

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“…Given the well understood demographic characteristics of ALSPAC 23 , 24 and notwithstanding ancestry-specific deviations in frequency, it is reasonable to suggest that as many as 1 in every 337 people in the UK could carry a heterozygous LoF mutation in the MC4R gene. These estimates are approximately double the previous reports 15 , 29 – 31 and whilst based on assumptions on the properties of our sample, results here allow a recalibration of prevalence estimates more broadly.…”

Section: Discussionsupporting

confidence: 58%

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Wade

Lam

Melvin

et al. 2021

Nat Med

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Mutations in the melanocortin 4 receptor gene ( MC4R ) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterised all non-synonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss of function (LoF) mutations in MC4R was ~1/337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and non-carriers of LoF mutations were 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m 2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

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Section: Discussionsupporting

confidence: 58%

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Wade

Lam

Melvin

et al. 2021

Nat Med

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“…Interestingly, Lubrano-Berthelier et al25 found a higher frequency of MC4R pathogenic mutations (2.6%) in French adult subjects with severe obesity. Tunç et al6 also reported an elevated prevalence of MC4R mutations (8.5%) in obese children and adolescence from Turkey. These findings suggest that the high frequency of MC4R mutation associated with nonsyndromic monogenic obesity occurs only in certain ethnic groups.…”

Section: Discussionmentioning

confidence: 92%

“…The etiology of obesity is multifactorial, caused by an interaction of environmental factors with many variants of minor effect in multiple genes; however, rare monogenic forms caused by mutations with major effect in a single gene were also identified 5. Among the monogenic types of nonsyndromic obesity, mutations in melanocortin 4 receptor gene ( MC4R ) are considered the most common cause of this disorder (OMIM*155541) 65…”

Section: Introductionmentioning

confidence: 99%

<p>Identification of the <em>MC4R</em> start lost mutation in a morbidly obese Brazilian patient</p>

Fonseca¹,

Abreu²,

Zembrzuski³

et al. 2019

DMSO

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Background Melanocortin 4 receptor gene ( MC4R ) is an important regulator of food intake, body weight, and blood pressure. Mutations in MC4R are associated with the most common form of nonsyndromic monogenic obesity. MC4R variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding MC4R variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the MC4R gene in a Brazilian cohort of severely obese adults and to investigate the phenotype–genotype correlation within MC4R variant carriers. Methods This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0–11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12–21 years). The entire coding region of MC4R gene was screened by Sanger sequencing. Results As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of MC4R . It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with MC4R missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying MC4R variants had higher median of waist–hip ratio when compared to noncarriers ( P =0.048). These missense variants were also associated with hypertension ( P =0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers ( P =0.020 and P =0.065, respectively). Val103Ile was also associated with hypertension ( P =0.003). Conclusion This study showed the prevalence of MC4R variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of MC4R on body fat distribution and blood pressure.

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“…These estimates are approximately double the previous report in an adult population-based cohort of European ancestry 15 and currently approximates to 200,000 UK residents. In a more speculative approach, if this figure were to be true for populations worldwide (which is not inconsistent with published data 28-30 ), up to 22 million people could carry a heterozygous LoF mutation in MC4R .…”

Section: Discussionmentioning

confidence: 91%

Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort

Wade

Lam

Melvin

et al. 2020

Preprint

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Mutations in the melanocortin 4 receptor gene (MC4R) have frequently been reported in severe early-onset human obesity but the prevalence and extent of phenotypic impact of such mutations are unclear. In a large UK birth cohort, we found that 17 of 5724 unrelated participants (~1/337; 0.30%) were heterozygous for functionally deleterious mutations. At age 18 years, the mean difference in body weight, body mass index (BMI) and fat mass was 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively, in carriers of loss of function (LoF) mutations compared to non-LoF carriers. Carriage of LoF mutations increased adiposity from as early as 5 years. MC4R LoF was associated with an impact on BMI at age 18 years that was approximately double that of a genome-wide polygenic risk score (comparing the upper 10th and lower 90th percentile). An extrapolation of incidence for MC4R LoF mutations from this birth cohort suggests that up to ~200,000 people in the UK are likely to carry such mutations. This frequency, combined with the substantial impact of these variants on adiposity, has implications for public health, and drug development.

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Melanocortin-4 Receptor Gene Mutations in a Group of Turkish Obese Children and Adolescents

Cited by 14 publications

References 22 publications

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

<p>Identification of the <em>MC4R</em> start lost mutation in a morbidly obese Brazilian patient</p>

Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort

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