Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations

Giudice, Emanuele Miraglia del; Cirillo, Grazia; Santoro, Nicola; D'Urso, L; Carbone, M. D.; Toro, R.; Perrone, Laura

doi:10.1038/sj.ijo.0801485

Cited by 59 publications

(31 citation statements)

References 28 publications

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“…In a French study, R236G was present in 1.65% (3 of 182) of individuals (mean BMI Ͼ31.8 kg/m 2 ) in association with early-onset obesity and in 1.04% of controls (8 ). R236G was also detected in 1.15% (1 of 87) of obese Italian children (BMI standard deviation score ϭ 3.43) (9 ). Interestingly, it was also identified in 0.6% (1 of 156) of individuals in a Danish study of juvenile-onset obesity (BMI ϭ 35.8 kg/m 2 ) diagnosed when the individual was ϳ20 years of age (7 ), which coincides with our heterozygous carrier of this variant, a female diagnosed as obese at 21 years of age.…”

Section: Discussionmentioning

confidence: 99%

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Buono

Pasanisi

Nardelli³

et al. 2005

Clinical Chemistry

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Background:The genetic characterization of obese individuals could clarify the molecular mechanisms underlying body weight regulation and lead to targeted therapy. Here we report variants of the proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) genes detected in severely obese adults living in southern Italy. Methods: A total of 196 unrelated nondiabetic severely obese individuals [111 females and 85 males; mean (SD) age, 32.2 (11.5) years; mean body mass index, 48.8 (8.1) kg/m 2 ] and 100 normal-weight healthy volunteers (34 males and 66 females) entered the study. POMC and MC4R were genotyped by sequencing analysis. Leptin, insulin, glucose, and the lipid profile were measured in fasting serum samples. We used the protein truncation test to verify the stop-codon mutation. Anthropometric measurements, sitting blood pressure, and heart rate were also recorded. Results: Of the obese participants, 1.5% had mutations in POMC exon 3 (new mutations, P231L and E244X; known, R236G) and 2.5% had MC4R mutations (new mutations, W174C, Q43X, S19fsX51, and I317V; known, A175T). These mutations were not present in the controls. Gene polymorphisms were identified in similar percentages of severely obese and nonobese individu-

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Section: Discussionmentioning

confidence: 99%

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Buono

Pasanisi

Nardelli³

et al. 2005

Clinical Chemistry

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“…With respect to nonsyndromic obesity, four mutation screening studies involving 601 nonsyndromic obese subjects have shown missense or nonsense mutations in just 7 individuals, implying that coding sequence variation in POMC is a very uncommon cause of nonsyndromic obesity (15)(16)(17)(18). Two genome-screening studies, in French obese sibling pairs and in Mexican-American ex- tended families, suggested strong evidence for linkage of plasma leptin levels to the region of chromosome 2 harboring the POMC gene (19,20).…”

Section: Discussionmentioning

confidence: 99%

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

et al. 2005

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Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P ‫؍‬ 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation. Diabetes 54: 2492-2496, 2005A bdominal obesity is a major risk factor for type 2 diabetes, coronary heart disease (CHD), colon cancer, and several other common and serious conditions. Although the definition of obesity typically relies on BMI, several studies suggest that, with respect to risk stratification, measurement of the waist-to-hip ratio (WHR) may be a superior predictor both of type 2 diabetes and CHD, possibly because of specific metabolic abnormalities accompanying central, rather than generalized, obesity (1,2). Both WHR and BMI are heritable traits, and various studies suggest that genes account for 25-70% of the observed variability (3,4).Melanocortin signaling in the hypothalamus plays a central role in the control of energy homeostasis. The proopiomelanocortin (POMC) gene is expressed in response to leptin signaling by neurons of the hypothalamic arcuate nucleus. Intracellular posttranslational processing of the POMC propeptide by prohormone convertase 2 leads to the production in these neurons of ␣-, ␤-, and ␥-melanocyte-stimulating hormones. These peptides signal to downstream target neurons in the lateral hypothalamus that express the melanocortin receptors MC3R and MC4R with resultant decrease in food intake and increase in energy expenditure (5). Rare mutations in the POMC gene cause monogenic, severe, early-onset obesity in humans; however, the influence of common polymorphisms in POMC on obesity phenotypes in less extreme individuals is unclear (6). POMC is also a precursor of adrenocorticotrophic hormone (ACTH); pathological ACTH excess results in severe central obesity. We have investigated the role of common polymorphisms of the POMC gene on abdominal obesity in a large family study. RESEARCH DESIGN AND METHODSSubject collection and phenotyping. The collect...

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“…15 Polymerase chain reaction (PCR) products were screened using the single-strand conformation polymorphism (SSCP) analysis as previously described. 19 Subsequently, MC4R amplification was repeated using the same primer pairs in a buffer containing 20 mM Tris -HEPES, 10 mM KCl, 10 mM ammonium sulfate, 2 mM MgCl 2 and the Amplitaq Gold DNA polymerase (Perkin Elmer, USA). PCR products (3 ml) were analysed by a Wave (Transgenomic, USA) denaturing high-performance liquid chromatography (DHPLC) system.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2002

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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.

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Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations

Cited by 59 publications

References 28 publications

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Association Between Common Polymorphisms of the Proopiomelanocortin Gene and Body Fat Distribution

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

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