{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:13:31Z","timestamp":1777652011899,"version":"3.51.4"},"reference-count":36,"publisher":"American Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3546,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5\u201320 years) and adulthood (ages 20\u201345 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-0708","type":"journal-article","created":{"date-parts":[[2011,11,22]],"date-time":"2011-11-22T06:20:51Z","timestamp":1321942851000},"page":"250-257","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":56,"title":["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"],"prefix":"10.2337","volume":"61","author":[{"given":"Marie S.","family":"Thearle","sequence":"first","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunhua L.","family":"Muller","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meghan","family":"Mullins","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"AbdusSamad","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Tran","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C.","family":"Knowler","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clifton","family":"Bogardus","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Krakoff","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie J.","family":"Baier","sequence":"additional","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","published-online":{"date-parts":[[2011,12,12]]},"reference":[{"key":"2022031210293414100_B1","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1093\/hmg\/ddn431","article-title":"Association of functionally significant melanocortin-4 but not melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study","volume":"18","author":"Calton","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2022031210293414100_B2","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1210\/jc.2007-0352","article-title":"Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis","volume":"92","author":"Hainerov\u00e1","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B3","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1210\/jc.2005-2056","article-title":"Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany","volume":"91","author":"Hinney","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B4","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.2337\/db08-0577","article-title":"Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant","volume":"57","author":"Krakoff","year":"2008","journal-title":"Diabetes"},{"key":"2022031210293414100_B5","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1210\/jc.2005-1411","article-title":"Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating","volume":"91","author":"Lubrano-Berthelier","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B6","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.2337\/db08-0153","article-title":"Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees","volume":"57","author":"Stutzmann","year":"2008","journal-title":"Diabetes"},{"key":"2022031210293414100_B7","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1172\/JCI9397","article-title":"Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency","volume":"106","author":"Farooqi","year":"2000","journal-title":"J Clin Invest"},{"key":"2022031210293414100_B8","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1056\/NEJMoa022050","article-title":"Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene","volume":"348","author":"Farooqi","year":"2003","journal-title":"N Engl J Med"},{"key":"2022031210293414100_B9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1172\/JCI9238","article-title":"Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity","volume":"106","author":"Vaisse","year":"2000","journal-title":"J Clin Invest"},{"key":"2022031210293414100_B10","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1210\/jc.2004-0497","article-title":"Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity","volume":"90","author":"Larsen","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B11","doi-asserted-by":"crossref","first-page":"1543S","DOI":"10.1093\/ajcn\/53.6.1543S","article-title":"Obesity in the Pima Indians: its magnitude and relationship with diabetes","volume":"53","author":"Knowler","year":"1991","journal-title":"Am J Clin Nutr"},{"key":"2022031210293414100_B12","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.2337\/dc06-2010","article-title":"Changing patterns of type 2 diabetes incidence among Pima Indians","volume":"30","author":"Pavkov","year":"2007","journal-title":"Diabetes Care"},{"key":"2022031210293414100_B13","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1086\/302061","article-title":"An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians","volume":"63","author":"Hanson","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2022031210293414100_B14","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.2337\/diabetes.53.5.1181","article-title":"Genetic studies of the etiology of type 2 diabetes in Pima Indians: hunting for pieces to a complicated puzzle","volume":"53","author":"Baier","year":"2004","journal-title":"Diabetes"},{"key":"2022031210293414100_B15","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.2337\/dc06-0138","article-title":"Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S","volume":"29","author":"Schulz","year":"2006","journal-title":"Diabetes Care"},{"key":"2022031210293414100_B16","doi-asserted-by":"crossref","first-page":"E33","DOI":"10.1542\/peds.109.2.e33","article-title":"Early excess weight gain of children in the Pima Indian population","volume":"109","author":"Lindsay","year":"2002","journal-title":"Pediatrics"},{"key":"2022031210293414100_B17","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF01219743","article-title":"Islet cell antibodies and diabetes mellitus in Pima Indians","volume":"17","author":"Knowler","year":"1979","journal-title":"Diabetologia"},{"key":"2022031210293414100_B18","doi-asserted-by":"crossref","first-page":"22939","DOI":"10.1074\/jbc.M211326200","article-title":"Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity","volume":"278","author":"Nijenhuis","year":"2003","journal-title":"J Biol Chem"},{"key":"2022031210293414100_B19","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/hmg\/ddg057","article-title":"Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms","volume":"12","author":"Yeo","year":"2003","journal-title":"Hum Mol Genet"},{"key":"2022031210293414100_B20","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.2337\/diabetes.53.10.2696","article-title":"Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians","volume":"53","author":"Ma","year":"2004","journal-title":"Diabetes"},{"key":"2022031210293414100_B21","first-page":"1","article-title":"CDC growth charts: United States","author":"Kuczmarski","year":"2000","journal-title":"Adv Data"},{"issue":"Suppl. 1","key":"2022031210293414100_B22","first-page":"S5","article-title":"Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus","volume":"26","year":"2003","journal-title":"Diabetes Care"},{"key":"2022031210293414100_B23","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.bbrc.2007.10.170","article-title":"Role of third intracellular loop of the melanocortin 4 receptor in the regulation of constitutive activity","volume":"365","author":"Kim","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031210293414100_B24","first-page":"604","article-title":"Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children","volume-title":"Obesity (Silver Spring)","author":"van den Berg","year":"2011"},{"key":"2022031210293414100_B25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa0803085","article-title":"Modulation of blood pressure by central melanocortinergic pathways","volume":"360","author":"Greenfield","year":"2009","journal-title":"N Engl J Med"},{"key":"2022031210293414100_B26","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/ajpa.1330920406","article-title":"Obesity in Pima Indians: large increases among post-World War II birth cohorts","volume":"92","author":"Price","year":"1993","journal-title":"Am J Phys Anthropol"},{"key":"2022031210293414100_B27","doi-asserted-by":"crossref","first-page":"e1000284","DOI":"10.1371\/journal.pmed.1000284","article-title":"Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth","volume":"7","author":"Elks","year":"2010","journal-title":"PLoS Med"},{"key":"2022031210293414100_B28","doi-asserted-by":"crossref","first-page":"E181","DOI":"10.1210\/jc.2010-1369","article-title":"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","volume":"96","author":"Martinelli","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B29","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1093\/hmg\/ddp504","article-title":"Life course variations in the associations between FTO and MC4R gene variants and body size","volume":"19","author":"Hardy","year":"2010","journal-title":"Hum Mol Genet"},{"key":"2022031210293414100_B30","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/oby.2008.422","article-title":"Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene","volume":"17","author":"Reinehr","year":"2009","journal-title":"Obesity (Silver Spring)"},{"key":"2022031210293414100_B31","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1093\/hmg\/ddm132","article-title":"Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene","volume":"16","author":"Stutzmann","year":"2007","journal-title":"Hum Mol Genet"},{"key":"2022031210293414100_B32","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1210\/jc.2009-2297","article-title":"Sympathetic function in human carriers of melanocortin-4 receptor gene mutations","volume":"95","author":"Sayk","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210293414100_B33","first-page":"679","article-title":"Gynecological aspects of female familial dysautonomia","volume":"2","author":"Maayan","year":"2000","journal-title":"Isr Med Assoc J"},{"key":"2022031210293414100_B34","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/ng.714","article-title":"Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies","volume":"42","author":"Elks","year":"2010","journal-title":"Nat Genet"},{"key":"2022031210293414100_B35","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.peptides.2009.03.006","article-title":"Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling","volume":"30","author":"Chai","year":"2009","journal-title":"Peptides"},{"key":"2022031210293414100_B36","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.peptides.2010.06.028","article-title":"Melanocortin-4 receptor activation promotes insulin-stimulated mTOR signaling","volume":"31","author":"Chai","year":"2010","journal-title":"Peptides"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/61\/1\/250\/558432\/250.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/61\/1\/250\/558432\/250.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:27:18Z","timestamp":1667406438000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/61\/1\/250\/15888\/Greater-Impact-of-Melanocortin-4-Receptor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,12]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2011,12,12]]},"published-print":{"date-parts":[[2012,1,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db11-0708","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,12]]}}}