Identification and functional analysis of novel human melanocortin-4 receptor variants.

Abstract

Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting results in mice that develop maturity-onset obesity, hyperinsulinemia, and hyperglycemia. These phenotypes resemble common forms of human obesity, which are late-onset and frequently accompanied by NIDDM. It is not clear whether sequence variation of the MC4-R gene contributes to obesity in humans. Therefore, we examined the human MC4-R gene polymorphism in 190 individuals ascertained on obesity status. Three allelic variants were identified, including two novel ones, Thr112Met and Ile137Thr. To analyze possible functional alterations, the variants were cloned and expressed in vitro and compared with the wild-type receptor. One of the novel variants, Ile137Thr, identified in an extremely obese proband (BMI 57), was found to be severely impaired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.

Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children

“…Three adults were heterozygous for the Val103Ile variant and one for the Thr112Met variant, two previously reported polymorphisms. 9,18 Neither the third known polymorphism, Ile251Leu, 19 nor MC4R analysis in Belgian obese children and adults S Beckers et al pathogenic mutations in MC4R were found in our cohort of morbidly obese adult patients. The cohort of 123 children and adolescents was also screened for MC4R mutations.…”

“…35 However, functional analysis of all three polymorphisms did not indicate a difference to wild type MC4R. 14,15,18,34 …”

“…Mutation screening of MC4R did reveal three different sequence variants in our population. All three were previously reported: a G-A nucleotide change at position 307 resulting in the substitution of Val103 with Ile, 9 a C335T single nucleotide change which leads to a Thr112Met aminoacid substitution 18 and finally the Ile251Leu substitution resulting from the A751C nucleotide change. 19 In our study, the frequencies of the rare alleles of the latter two polymorphisms (Thr112Met 0.46%, Ile251Leu 0.92%) are in line with those reported previously.…”

“…However, when no selection for age of onset was made at the start of the study, pathogenic MC4R mutations were absent 9,10 or frequencies were low (0.5-2.1%). 18,[25][26][27][28][29][30][31][32][33][34] However, the variation in the frequency of mutations can also be due to differences in ethnicity. There is a clear trend for higher frequencies in the British population, [20][21][22] while lower frequencies are observed in other populations, including Italians 26,31 and Germans.…”

Controle neuroendócrino do peso corporal: implicações na gênese da obesidade

“…As primeiras descrições foram publicadas em outubro de 1998 por dois grupos diferentes na mesma edição da revista Nature Genetics (53,54). A partir daí, várias mutações foram descritas, com freqüências variando de menos de 0,5% a 5,8% (55)(56)(57)(58)(59)(60)(61)(62). As disparidades na prevalência de mutações patogênicas no MC4R, resultam, em parte, das diferenças étnicas e dos critérios de…”