Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity
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E Miraglia Del Giudice1, G Cirillo, V Nigro
1Dipartimento de Pediatria, Seconda Università di Napoli, Napoli, Italy. emanuele.miraglia@unina2.it
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+/-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)=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.
Insights
Melanocortin-4 receptor (MC4R) mutations are a rare cause of early-onset obesity in Southern Italy, found in less than 0.5% of cases. Genetic background may influence MC4R mutation impact on obesity.
Area of Science:
- Genetics
- Endocrinology
- Obesity Research
Background:
- Melanocortin-4 receptor (MC4R) mutations are a significant genetic cause of obesity.
- MC4R mutations are implicated in over 4% of early-onset obesity cases in some populations.
Purpose of the Study:
- To investigate the prevalence of MC4R gene mutations in Southern Italian children with early-onset obesity.
- Screen for mutations in the MC4R coding region.
Main Methods:
- Studied 208 unrelated obese children and adolescents.
- Employed single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) for mutation screening.
- Performed automatic sequencing for identified aberrant patterns.
Main Results:
- Identified one novel missense mutation (C142T) and one known polymorphism (Vall03Ile).
- The novel mutation was found in a severely obese 15-year-old girl and segregated with obesity across three generations.
- The mutation was absent in the control population, indicating a prevalence of <0.5% in the studied cohort.
Conclusions:
- MC4R mutations are infrequent causes of obesity in Southern Italian children (<0.5%).
- The Mediterranean genetic background may reduce the penetrance of MC4R mutations in common obesity.
- Further research is needed to understand the role of MC4R in obesity within diverse populations.
