Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations.
BACKGROUND
Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis.


OBJECTIVE
To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity.


METHODS
Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7+/-2.5 y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern.


RESULTS
Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the beta-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele.


CONCLUSIONS
Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. International Journal of Obesity (2001) 25, 61-67
Miraglia del Giudice
E
E
Department of Pediatrics, Second University of Naples, Via S.Andrea delle Dame no. 4, 80138 Napoli, Italy. emanuele.miraglia@unina2.it
Cirillo
G
G
Santoro
N
N
D'Urso
L
L
Carbone
M T
MT
Di Toro
R
R
Perrone
L
L
D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D003062:Codon; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D020738:Leptin; D008297:Male; D008967:Molecular Biology; D020125:Mutation, Missense / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D021382:Protein Sorting Signals / Q000235:genetics; D014178:Translocation, Genetic
D003062:Codon; D020738:Leptin; D021382:Protein Sorting Signals; D011333:Pro-Opiomelanocortin