Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity

Abstract

BACKGROUND: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity. OBJECTIVES: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity. SUBJECTS AND METHODS: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5 AE 2.6 y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and=or DHPLC pattern was performed. RESULTS: One novel missense mutation and one previously described polymorphism (Vall03Ile) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI) ¼ 35 kg=m 2 ) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population. CONCLUSIONS: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood.

A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population

“…Functional studies showed that many of the missense muations also lead to a loss of function of the MC4R. 5,6,8,13 However, other mutations (ie Thr-11-Ser, Arg-18-Cys) and two polymorphisms (Val-103-Ile, Ile-251-Leu) did not modify the function of the MC4R in vitro. 5,7 It has been estimated that 2-4% of extremely obese individuals harbor functionally relevant MC4R mutations.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] Several mutations of the MC4R, mainly one nonsense (Tyr-35-Stop) and three frameshift mutations (732-733insGATT, 631-634delCTCT, 47-48insG) can be considered loss-of-function mutations and are associated with dominant inheritance of obesity. Functional studies showed that many of the missense muations also lead to a loss of function of the MC4R.…”

Increased constraints on MC4R during primate and human evolution

“…Many studies have screened the MC4R locus in thousands of obese probands to identify reduced or loss of function mutations associated with dominantly inherited obesity (Biebermann et al 2003;Branson et al 2003;Dubern et al 2001;Farooqi et al 2003;Gu et al 1999;Hinney et al 2003;Hinney et al 1999;Kobayashi et al 2002;Larsen et al 2005;Lubrano-Berthelier et al 2003;Miraglia Del Giudice et al 2002;Santini et al 2004;Srinivasan et al 2004;Vaisse et al 2000;Valli-Jaakola et al 2004;Yeo et al 2003). To date about 90 such mutations have been identiWed and functionality determined by an in vitro cAMP accumulation assay.…”

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

“…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.…”