Several Mutations in the Melanocortin-4 Receptor Gene Including a Nonsense and a Frameshift Mutation Associated with Dominantly Inherited Obesity in Humans

Abstract

The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.

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

“…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. Based on metaanalysis of all studies listed in Table 4, there is no significant difference between controls and cases for these two polymorphisms.…”

“…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.…”

“…A number of groups detected mutations at high frequency among obese patients. [12][13][14][15][19][20][21][22][23][24] As shown in Table 3, the frequency of pathogenic MC4R mutations in these populations ranged from 2.5% 21 to as high as 6.3%. 12 These studies clearly focused on children with severe obesity and adults with reported early onset of obesity.…”

AgRP(83–132) and SHU9119 differently affect activity-based anorexia

“…Polymorphisms in the MC4-R gene (Val103Ile, Ile251Leu) and AgRP gene (Ala67Thr) have also been found in AN patients. Although the occurrence of the MC4-R polymorphism was not different from a control population (Hinney et al, 1999), the AgRP polymorphism occurred more frequently in a population of AN patients compared to controls (Vink et al, 2001) and was associated with low body weight in two other populations (Argyropoulos et al, 2002;Marks et al, 2004).…”

a-MSH enhances activity-based anorexia

“…Polymorphisms in the MC4R gene (Val103Ile, Ile251Leu) and AGRP gene (Ala67Thr) have also been described in populations of AN patients. Although the occurrence of the MC4R polymorphisms was not different from a control population [24], the AGRP polymorphism occurred more frequently in a population of AN patients as compared to controls [47] and was associated with low body weight in two other populations [3,33].…”