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Objective To explore the possible correlation between the genetic variations of the melanocortin receptors (MCRs, including MC2R, MC3R and MC4R) and adrenocorticotropic hormone (ACTH) responsiveness in patients with infantile spasms, and to investigate the function of single nucleotide polymorphism (SNP) found in this study. Methods Direct sequencing method was used to test variations and polymorphisms in the promoter and coding regions of the MC2R, MC3R and MC4R gene. Haplotypes were structured by using SHEsis and Haploview3.32 programs to analyze the distribution frequencies of polymorphism genotypes, alleles and structured haplotypes in Chinese patients with infantile spasms and normal controls. The association between ACTH responsiveness and genetic variations was also assessed. Results Four SNPs were identified in the MC2R promoter region, one of which was new ⁃found locus named ⁃ 2T > C. Three SNPs (rs1893220, rs2186944 and ⁃ 2T > C) showed a significant difference between the cases and controls (P = 0.04, 0.02, 0.01). The common haplotype TCCT may give protection against the development of infantile spasms (P = 0.00). Besides, TCCT carriers were more sensitive to ACTH therapy than non⁃carriers (P = 0.00). The in vitro study proved that the translational efficiency of TCCT promoter in MC2R gene was four times higher than that of TCCC promoter (P = 0.00). MC2R expression assay showed a 5⁃fold increase in the TCCT promoter in presence of ACTH, compared with that in absence of ACTH (P = 0.00). However, responsiveness to ACTH in expression by TCCC promoter showed only 1.50⁃fold increase after ACTH stimulation (P > 0.05). The SNP rs11872992 in MC4R gene was related to the development of infantile spasms, as the efficiency of TC genotype in cases was lower than that of normal controls (P = 0.00). The ACTH therapy results of T⁃allele⁃carriers were better than that of non⁃T⁃allele⁃carriers (P = 0.01). The difference of SNP distribution frequencies in MC3R gene was not statistically significant (P > 0.05). Conclusion The study revealed an association between polymorphism in MCRs (MC2R and MC4R) promoter and the development of infantile spasms, and ACTH responsiveness in patients with infantile spasms. These findings may provide a clue for clinicians to find an early predictive marker for the responsiveness to ACTH and improve the understanding of pathogenesis in infantile spasms. DOI：10.3969/j.issn.1672⁃6731.2012.05.012