Received on January 5, 2005
Accepted on May 4, 2005

Molecular Diagnostics and Genetics

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

¹ Facoltà di Scienze Motorie, Università degli Studi Parthenope di Napoli, Naples, Italy, Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE Biotecnologie Avanzate S.C. a r.l., Naples, Italy.
² Dipartimento di Medicina Clinica e Sperimentale-CISRO, Università di Napoli Federico II, Naples, Italy
³ Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
⁴ Dipartimento di Biochimica e Biotecnologie Mediche, and CEINGE Biotecnologie Avanzate S.C. a r.l., Naples, Italy
⁵ CEINGE Biotecnologie Avanzate S.C. a r.l., Naples, Italy
⁶ CEINGE Biotecnologie Avanzate S.C. a r.l., Naples, Italy, and Dipartimento S.P.E.S., Università del Molise, Campobasso, Italy

^* To whom correspondence should be addressed. E-mail: sacchetti{at}dbbm.unina.it.

Background: The genetic characterization of obese participants 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/m²] 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 participants, i.e., respectively, 52.5% and 51% (POMC) and 1% and 2% (MC4R).

Conclusions: We detected 2 new POMC mutations and 4 new MC4R mutations in a large number of severely obese adults living in southern Italy. These mutations, not present in normal-weight participants, are further evidence that defects in the melanocortin pathway are related to severe obesity.