Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
30
10
2020
accepted:
12
04
2021
pubmed:
29
5
2021
medline:
20
8
2021
entrez:
28
5
2021
Statut:
ppublish
Résumé
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 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous 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 in 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 noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m
Identifiants
pubmed: 34045736
doi: 10.1038/s41591-021-01349-y
pii: 10.1038/s41591-021-01349-y
pmc: PMC7611835
mid: EMS136341
doi:
Substances chimiques
Receptor, Melanocortin, Type 4
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1088-1096Subventions
Organisme : Wellcome Trust
ID : 095515/Z/11/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 208363/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202802
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S017593/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202802/Z/16/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18281/A19169
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15018
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102215/2/13/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204813/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098497/Z/12/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Références
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
pubmed: 7984236
doi: 10.1038/372425a0
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).
pubmed: 9019399
doi: 10.1016/S0092-8674(00)81865-6
Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).
pubmed: 9202122
doi: 10.1038/43185
Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112 (1998).
pubmed: 9771698
doi: 10.1038/2404
Clément, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998).
pubmed: 9537324
doi: 10.1038/32911
Gantz, I. et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15174–15179 (1993).
pubmed: 8392067
doi: 10.1016/S0021-9258(18)82452-8
Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308 (1994).
pubmed: 7854347
Cowley, M. A. et al. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, 155–163 (1999).
pubmed: 10677034
doi: 10.1016/S0896-6273(00)80829-6
Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).
pubmed: 11373681
doi: 10.1038/35078085
Haynes, W. G., Morgan, D. A., Djalali, A., Sivitz, W. I. & Mark, A. L. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 33, 542–547 (1999).
pubmed: 9931162
doi: 10.1161/01.HYP.33.1.542
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
pubmed: 8990120
doi: 10.1038/385165a0
Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114 (1998).
pubmed: 9771699
doi: 10.1038/2407
Farooqi, I. S. et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest. 106, 271–279 (2000).
pubmed: 10903343
pmcid: 314308
doi: 10.1172/JCI9397
Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253–262 (2000).
pubmed: 10903341
pmcid: 314306
doi: 10.1172/JCI9238
Hinney, A. et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J. Clin. Endocrinol. Metab. 91, 1761–1769 (2006).
pubmed: 16492696
doi: 10.1210/jc.2005-2056
Dempfle, A. et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J. Med. Genet. 41, 795–800 (2004).
pubmed: 15466016
pmcid: 1735595
doi: 10.1136/jmg.2004.018614
Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348, 1085–1095 (2003).
pubmed: 12646665
doi: 10.1056/NEJMoa022050
Collet, T.-H. et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol. Metab. 6, 1321–1329 (2017).
pubmed: 29031731
pmcid: 5641599
doi: 10.1016/j.molmet.2017.06.015
Stutzmann, F. et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 57, 2511–2518 (2008).
pubmed: 18559663
pmcid: 2518504
doi: 10.2337/db08-0153
Turcot, V. et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat. Genet. 50, 26–41 (2018).
pubmed: 29273807
doi: 10.1038/s41588-017-0011-x
Gonçalves, J. P. L., Palmer, D. & Meldal, M. MC4R agonists: structural overview on antiobesity therapeutics. Trends Pharmacol. Sci. 39, 402–423 (2018).
pubmed: 29478721
doi: 10.1016/j.tips.2018.01.004
Apovian, C. M. The obesity epidemic–understanding the disease and the treatment. N. Engl. J. Med. 374, 177–179 (2016).
pubmed: 26760089
doi: 10.1056/NEJMe1514957
Boyd, A. et al. Cohort profile: the ‘children of the 90s’–the index offspring of the Avon Longitudinal Study of Parents and Children. Int. J. Epidemiol. 42, 111–127 (2013).
pubmed: 22507743
doi: 10.1093/ije/dys064
Fraser, A. et al. Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. Int. J. Epidemiol. 42, 97–110 (2012).
pubmed: 22507742
pmcid: 3600619
doi: 10.1093/ije/dys066
Cornish, R. P., Macleod, J., Boyd, A. & Tilling, K. Factors associated with participation over time in the Avon Longitudinal Study of Parents and Children: a study using linked education and primary care data. Int. J. Epidemiol. 50, 293–302 (2020).
pmcid: 7938505
doi: 10.1093/ije/dyaa192
Lotta, L. A. et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177, 597–607 (2019).
pubmed: 31002796
pmcid: 6476272
doi: 10.1016/j.cell.2019.03.044
Greenfield, J. R. et al. Modulation of blood pressure by central melanocortinergic pathways. N. Engl. J. Med. 360, 44–52 (2009).
pubmed: 19092146
doi: 10.1056/NEJMoa0803085
Khera, A. V. et al. Polygenic prediction of weight and obesity trajectories from birth to adulthood. Cell 177, 587–596 (2019).
pubmed: 31002795
pmcid: 6661115
doi: 10.1016/j.cell.2019.03.028
Krakoff, J. et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes 57, 3267–3272 (2008).
pubmed: 18835933
pmcid: 2584132
doi: 10.2337/db08-0577
Thearle, M. S. et al. Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians. Diabetes 61, 250–257 (2012).
pubmed: 22106157
doi: 10.2337/db11-0708
Tunç, S. et al. Melanocortin-4 receptor gene mutations in a group of Turkish obese children and adolescents. J. Clin. Res. Pediatr. Endocrinol. 9, 216–221 (2017).
pubmed: 28218067
pmcid: 5596802
doi: 10.4274/jcrpe.4225
Martinelli, C. E. et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J. Clin. Endocrinol. Metab. 96, E181–E188 (2011).
pubmed: 21047921
doi: 10.1210/jc.2010-1369
Fry, A. et al. Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. Am. J. Epidemiol. 186, 1026–1034 (2017).
pubmed: 28641372
pmcid: 5860371
doi: 10.1093/aje/kwx246
Majithia, A. R. et al. Prospective functional classification of all possible missense variants in PPARG. Nat. Genet. 48, 1570–1575 (2016).
pubmed: 27749844
pmcid: 5131844
doi: 10.1038/ng.3700
Chami, N., Preuss, M., Walker, R. W., Moscati, A. & Loos, R. J. F. The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population. PLoS Med. 17, e1003196 (2020).
pubmed: 32692746
pmcid: 7373259
doi: 10.1371/journal.pmed.1003196
Baker, J. L., Olsen, L. W. & Sørensen, T. I. A. Childhood body-mass index and the risk of coronary heart disease in adulthood. N. Engl. J. Med. 357, 2329–2337 (2007).
pubmed: 18057335
pmcid: 3062903
doi: 10.1056/NEJMoa072515
Bjerregaard, L. G. et al. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N. Engl. J. Med. 378, 1302–1312 (2018).
pubmed: 29617589
doi: 10.1056/NEJMoa1713231
Richardson, T. G., Sanderson, E., Elsworth, B., Tilling, K. & Davey Smith, G. Use of genetic variation to separate the effects of early and later life adiposity on disease risk: Mendelian randomisation study. BMJ 369, m1203 (2020).
pubmed: 32376654
pmcid: 7201936
doi: 10.1136/bmj.m1203
Northstone, K. et al. The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019. Wellcome Open Res. 4, 51 (2019).
pubmed: 31020050
pmcid: 6464058
doi: 10.12688/wellcomeopenres.15132.1
Howe, L. D. et al. Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15. PLoS ONE 5, e15186 (2010).
pubmed: 21170348
pmcid: 2999567
doi: 10.1371/journal.pone.0015186
Wade, K. H. et al. Assessing the causal role of body mass index on cardiovascular health in young adults. Circulation 138, 2187–2201 (2018).
pubmed: 30524135
pmcid: 6250296
doi: 10.1161/CIRCULATIONAHA.117.033278
Lang, R. M. et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J. Am. Soc. Echocardiogr. 18, 1440–1463 (2005).
pubmed: 16376782
doi: 10.1016/j.echo.2005.10.005
Leckie, G. & Charlton, C. runmlwin: a program to run the MLwiN multilevel modeling software from within Stata. J. Stat. Softw. 52, 1–40 (2013).