Association report 161 Melanocortin-4 receptor molecular scanning and pro-opiomelanocortin R236G variant screening in binge eating disorder Alfonso Tortorella a , Palmiero Monteleone a , Emanuele Miraglia del Giudice b , Grazia Cirillo b , Laura Perrone b , Eloisa Castaldo a and Mario Maj a Psychiatric Genetics 2005, 15:161 a Department of Psychiatry, University of Naples SUN, Naples and b Department of Paediatrics ‘‘F. Fede ’’, University of Naples SUN, Naples, Italy. Correspondence and requests for reprints to Palmiero Monteleone, M.D., Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. e-mail: monteri@tin.it Accepted 9 June 2005 Recently, Branson et al. (2003) found that in a sample of severely obese study participants, all those carrying melanocortin-4 receptor (MC4R) gene mutations ful- filled the DSM-IV criteria for binge eating disorder (BED), suggesting that MC4R variants constitute a genetic vulnerability for BED. This hypothesis has been questioned because most of the MC4R mutations reported by Branson et al. are functionally inactive (Farooqi et al., 2003), and no increased rates of BED have been reported in other groups of MC4R mutation carriers extrapolated from small samples of obese patients in studies where the BED diagnosis was not made according to stringent DSM-IV criteria (Herpetz and Siffert, 2003; Hebebrand et al., 2004). Similarly to MC4R, mutations of the pro-opiomelanocortin (POMC) gene, which encodes for agonist ligands of MC4R, have been reported to confer an inherited susceptibility to obesity and could represent vulnerability factors for the develop- ment of BED. Because BED also occurs in non-obese participants and, so far, no study has assessed the prevalence of POMC gene variants in BED patients, we performed a MC4R mutational scanning and the screening of the POMC R236G substitution in 48 obese [body mass index (BMI) > 30 kg/m 2 ] and 10 non-obese (BMI < 30 kg/m 2 ) female patients, aged 18–58 years and fulfilling the DSM-IV criteria for BED as ascertained by the Structured Clinical Interview for DSM-IV Axis I disorders. As controls, 40 non-obese, healthy participants (BMI range = 18.50– 25.00 kg/m 2 ; age range = 18–39 years) were recruited. Genomic DNA was collected from nucleated white blood cells. Amplification of the MC4R coding region was done by polymerase chain reaction (PCR) and bi-directional sequencing of PCR products was performed with an automatic sequencer. The POMC gene R236G mutation was detected by PCR using the following two primers: POMC F (5 0 -GCACAGCCTGCTGGTGGCGGCC-3 0 ) and POMC R (5 0 -CTTGTGGCGTTCTTGATGATGG-3 0 ). The amplified products were digested with HhaI and were analysed on 2% agarose gel. Two polymorphisms, Val103Ile and Ile251Leu, and the missense mutation Ala175Thr of the MC4R gene were detected in BED patients. No patient exhibited the R236G missense mutation of the POMC gene. No variants of the MC4R and POMC genes were observed in the 40 controls. As previously described, the two polymorphisms of the MC4R are functionally inactive whereas the Ala175Thr mutation is responsible for a reduced functionality of the MC4R (Farooqi et al., 2003). This is the first time that this partially active mutation of the MC4R gene has been found in an obese woman who developed BED before becoming obese (BMI at the onset of BED was 29.00 kg/ m 2 ). Moreover, although the number of participants was certainly insufficient to reach significant conclusions on the possible association between the POMC gene R236G mutation and the development of BED, it is noteworthy that none of our BED patients carried this mutation. In conclusion, this study, comprising the largest sample of BED patients diagnosed according to stringent DSM-IV criteria and recruited independently from the occurrence of obesity, suggests that variations in the genes involved in the food intake regulating the melanocortin system do not represent a common genetic vulnerability for BED. References Branson R, Potoczna N, Kral JG, Lentes K-U, Hoehe MR, Horber FF (2003). Binge eating as a major phenotype of melanocortin-4 receptor gene mutations. N Engl J Med 348:1096–1103. Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, O’Rahilly S (2003). Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085–1095. Hebebrand J, Geler F, Dempfle A, Heinzel-Gutenbrunner M, Raab M, Wermter A-K, et al. (2004). Binge eating episodes are not characteristics of carriers of melanocortin-4 receptor gene mutations. Mol Psychiatry 9:796–800. Hepetz S, Siffert W (2003). Binge eating as a phenotype of melanocortin-4 receptor gene mutations. N Engl J Med 349:606–607. 0955-8829  c 2005 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.