Mutations in the Melanocortin 4 Receptor (MC4R) Gene in Obese Patients in Norway

Wangensteen, Teresia; Kolsgaard, Magnhild L Pollestad; Mattingsdal, Morten; Joner, Geir; Tonstad, Serena; Undlien, Dag E.; Retterstøl, Lars

doi:10.1055/s-0028-1102942

Cited by 25 publications

(17 citation statements)

References 25 publications

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“…The mutation was identified in heterozygous state in pediatric patients with severe childhood obesity. 11 It was not observed in adult obese patients.…”

Section: Mc4r (Omim#155541) Encodes a 332 Amino Acids Protein Possessmentioning

confidence: 92%

“…This finding is in contrast with a previous report wherein a single copy of the I69R mutation was sufficient to cause severe childhood-onset obesity. 11 Behavioral patterns in children, such as eating larger meals and viewing television have been shown to be associated with MC4R mutations to some extent. Similar behavior patterns have been seen in our case, which is in accordance with published reports.…”

Section: Mc4r (Omim#155541) Encodes a 332 Amino Acids Protein Possessmentioning

confidence: 99%

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MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

Khandelwal¹,

Birla²,

Sharma³

et al. 2017

US Endocrinology

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M elanocortin-4 receptor (MC4R; OMIM#155541) encodes a 332-amino acids protein possessing typical G-protein-coupled receptors' (GPCRs) structural design having three intact and functional domains, mutations which lead to the most recurrent type of monogenic obesity. Methods: We report here a case of a 5-year-old boy from Iraq who presented to the clinic for evaluation of progressive weight gain since he was 6 months of age. There were no symptoms of hypothalamic dysfunction except increase in appetite. His height was 120 cm (97th centile of the Centers for Disease Control and Prevention [CDC] growth chart, mid parental height was 50th centile), weight was 57 kg (>97th centile on CDC chart) and body mass index was 39.6 kg/m 2 (>97th centile on CDC chart). A monogenic cause of obesity was strongly suspected in view of early onset severe childhood obesity. Results: Mutation screening of MC4R revealed a homozygous isoleucine by arginie at codon 69 (I69R) mutation in the patient, while his father was heterozygous for this mutation. Conclusion: We describe a monogenic form of obesity with characteristic presentation due to I69R MC4R mutation inherited as an autosomal recessive condition. The finding is different from previous reports which have documented this mutation to be inherited in a dominant manner. The findings of the present study reiterate the complex nature of obesity with possible involvement of modifier genes and/or genetic heterogeneity in its causation. KeywordsMonogenic obesity, melanocortin-4 receptor (MC4R), hypothalamic obesity, childhood onset obesity, mutation, screening Disclosure: Shweta Birla, Deepak Khandelwal, Arundhati Sharma, and Rajesh Khadgawat have nothing to declare in relation to this article. No funding was received in the publication of this article.Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this case study.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Shweta Birla and Deepak Khandelwal contributed equally.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Obesity is a complex and multifactorial condition caused by various behavioral and environmental factors, socioeconomic background, and genetic susceptibility. The leptin-melanocortin system has a well-established role in energy homeostasis and deficiencies of the vital molecules of the pathway due to defects in the genes encoding those results into a monogenic form of obesity. 1The most recurrent type of mono...

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“…The mutation was identified in heterozygous state in pediatric patients with severe childhood obesity. 11 It was not observed in adult obese patients.…”

Section: Mc4r (Omim#155541) Encodes a 332 Amino Acids Protein Possessmentioning

confidence: 92%

Section: Mc4r (Omim#155541) Encodes a 332 Amino Acids Protein Possessmentioning

confidence: 99%

MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

Khandelwal¹,

Birla²,

Sharma³

et al. 2017

US Endocrinology

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“…MC4R mutations were first associated with severe obesity in humans in 1998 (Yeo et al, 1998;Vaisse et al, 1998), and subsequently with various other missense and nonsense MC4R mutations (Hinney et al, 1999;Ho and MacKenzie 1999;Gu et al, 1999;Farooqi et al, 2000;Vaisse et al, 2000;Farooqi et al, 2003). With an incidence ranging from 0.5% to 5% (Hinney et al, 2003;Yeo et al, 2003;Nijenhuis et al, 2003;Mergen et al, 2001;Miraglia Del Giudice et al, 2002;Sina et al, 1999;Lubrano-Berthelier et al, 2003a,b, 2006Srinivasan et al, 2004, Wangensteen et al 2009Santoro et al, Gene 457 (2010) [35][36][37][38][39][40][41] Abbreviations: AGRP, agouti-related protein; BMI, body mass index; CAT, chloramphenicol-acetyl-transferase; CRE, cAMP responsive element; HEK, human embryonic kidney; MC4R, melanocortin-4 receptor; NDP-α-MSH, [Nle 4 -D-Phe 7 ]-α-MSH; RSV, Rous sarcoma virus; TMH, transmembrane helix; wt, wild-type; PM, plasmamembrane; ER, endoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy

Alfieri

Pasanisi

Salzano

et al. 2010

Gene

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“…Mutations in the melanocortin-4 receptor (MC4R) are the commonest monogenic cause of human obesity with 1.6-5.8% prevalence and autosomal dominant heredity (Vaisse et al, 2000;Branson et al, 2003;Farooqi et al, 2003;Larsen et al, 2005;Rettenbacher et a., 2007;Wangensteen et al 2009). Carriers are afflicted with hyperphagia, hyperinsulinemia and increased fat mass with normal cortisol, gonadotropin, thyroid and sex steroid levels (Farooqi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

A novel missense mutation T101N in the melanocortin-4 receptor gene associated with obesity

Buchbinder

Bärtsch²,

Müller³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Mutations in the melanocortin-4 receptor (MC4R) are associated with severe obesity, independent of their effect on cortisol or thyroid-stimulating hormone levels. We examined a morbidly obese male (BMI = 62 kg/m 2 ) with a binge-eating disorder and eight family members for mutations in the MC4R gene and potential differences in leptin levels. Fifty healthy individuals served as controls. Sequence analysis revealed a novel heterozygous missense mutation (c.302 C>A, p.T101N) located in the second transmembrane domain of the receptor, which was not detected in controls. The Fisher exact test revealed an association between the T101N mutation and history of obesity (P < 0.05) in the family. The Kruskal-Wallis test showed an association between the mutation and the leptin/BMI ratio (P < 0.05), while there was no association between the T101N mutation and diabetes or arterial hypertension in the family. Although the available family was small, we could show a significant association between the heterozygous T101N mutation and obesity.

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Mutations in the Melanocortin 4 Receptor (MC4R) Gene in Obese Patients in Norway

Abstract: MC4R mutations are not a common cause of obesity in Norway and screening of obese patients does not appear to be warranted. The results are consistent with results from previous studies.

Cited by 25 publications

References 25 publications

MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy

A novel missense mutation T101N in the melanocortin-4 receptor gene associated with obesity

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