SYSTEMATIC MUTATION SCREENING OF THE PROOPIOMELANOCORTIN GENE - IDENTIFICATION OF SEVERAL GENETIC-VARIANTS INCLUDING 3 DIFFERENT INSERTIONS, ONE NONSENSE AND 2 MISSENSE POINT MUTATIONS IN PROBANDS OF DIFFERENTWEIGHT EXTREMES

Pro-opiomelanocortin (POMC) is the precursor of melanocortins (adrenoc orticotropin: ACTH, beta-endorphin, beta-lipotropin: beta-LPH, cortico tropin like intermediate peptide, alpha-, beta- and gamma-melanocyte-s timulating hormone: alpha-, beta- and gamma-MSH) some of which act in the brain to reduce food intake and are potential mediators of leptin action. Recently, three different mutations in the POMC gene (POMC) we re identified in two unrelated children that lead to early-onset extre me obesity, adrenal insufficiency, and red hair pigmentation (1). In t he present study we systematically screened the coding region of POMC in 96 extremely obese children and adolescents, 60 healthy underweight individuals and 46 patients with anorexia nervosa (AN) and identified several variants, a) A 9 and an 18 base pair insertion (9bp and 18bp: AGC AGC GGC and AGC AGC GGC AGC AGC GGC, respectively, between codon 73 and 74; 1,2). These in-frame variants lead to the insertion of thre e or six amino acids (Ser-Ser-Gly; Ser-Ser-Gly-Ser-Ser-Gly) carboxy-te rminal to gamma-MSH. Frequencies of the 9bp insertion allele varied be tween 3 and 5% among the different study groups (Pearson's chi(2) P>0. 5). b) Both an out-of-frame 6 bp insertion (within codon 176: GGG CCC) leading to the insertion of two amino acids (Arg-Ala) and a premature stop-codon (G-7316-T: Glu-180-Stop) within the gamma-LPH sequence wer e maternally inherited in an obese female proband. This proband inheri ted another missense mutation from her father (Glu-188-Gly). c) A miss ense mutation (G-7016-A; Asp-80-Asn) was observed in a single patient with AN who also harboured the 9bp insertion on a paternally derived h aplotype, d) The allelic co-occurence of two silent mutations (C-6982- T and C-7285-T) was detected in two obese subjects. e) Two further sil ent mutations (C-3832-T; C-7111-G) were detected in an underweight and an obese subject, respectively. We conclude that the POMC gene harbor s several different polymorphisms and mutations, none of which can rea dily be associated with the phenotypes under study.