Melanocortin-4 Receptor Gene: Case-Control Study and Transmission Disequilibrium Test Confirm that Functionally Relevant Mutations Are Compatible with a Major Gene Effect for Extreme Obesity

Abstract

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

“…It is thought to explain 2-6% of extremely obese childhood and adolescent cases (Farooqi et al, 2003;Hinney et al, 2003Hinney et al, , 2006Santini et al, 2004;Wang & Tao, 2011). The MC4R is a membrane-bound G-protein-coupled receptor that activates adenylate cyclase; in response to the α-melanocyte-stimulating hormone (α-MSH), MC4R induces production of cAMP (Stutzmann et al, 2008;Caruso et al, 2013).…”

“…Various missense, nonsense and frameshift MC4R mutations have been described (Human Mutation Database, HGMD; http://www.hgmd.cf.ac.uk) in a wide patient series with distinct ancestral origins. Currently, the clinical genotype-phenotype relationships in adult MC4R mutation carriers constitute an essential objective to define and corroborate the severity of each functional alteration (Hinney et al, 2003(Hinney et al, , 2006Lubrano-Berthelier et al, 2006;Wang & Tao, 2011). To date, more than 150 different MC4R mutations, mostly leading to a reduced function, have been detected in obese individuals (Hinney et al, 2013).…”

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

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

“…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.…”

“…However, two pathogenic mutations (Leu250Gln and Pro230Leu) were found to induce constitutive activity of the receptor. 14,15 Frameshift mutations, such as the originally described 4-bp insertion 7 and 4-bp deletion, 8 cause severe obesity due to haploinsufficiency.…”