Skin/hair/eye Pigmentation, Variation In, 9
A number sign (#) is used with this entry because variation in the gene encoding agouti signaling protein (ASIP; 600201) influences hair and eye pigmentation.
For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see 227220.
Molecular GeneticsIn mice and humans, binding of alpha-melanocyte-stimulating hormone (alpha-MSH; see 176830) to the melanocyte-stimulating-hormone receptor (MSHR), the protein product of the melanocortin-1 receptor (MC1R; 155555) gene, leads to the synthesis of eumelanin. In the mouse, ligation of MSHR by agouti signaling protein (ASP; 600201) results in the production of pheomelanin. The binding of ASP to MSHR precludes alpha-MSH-initiated signaling and thus blocks production of cAMP, leading to a downregulation of eumelanogenesis. The net result is increased synthesis of pheomelanin. Kanetsky et al. (2002) undertook to characterize the ASIP gene in a group of white subjects to assess whether ASIP was a determinant of human pigmentation and whether this gene is associated with increased melanoma risk. They found no evidence of coding region sequence variation in ASIP, but detected an 8818A-G polymorphism in the 3-prime untranslated region (rs6058017; 600201.0001). They genotyped 746 participants in a study of melanoma susceptibility for this polymorphism. Among 147 healthy controls, the frequency of the G allele was 0.12. Carriage of the G allele was significantly associated with dark hair (odds ratio 1.8) and brown eyes (odds ratio 1.9) after adjusting for age, gender, and disease status. This was said to be the first report of an association of ASIP with specific human pigmentation characteristics. It remained to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk.
Sulem et al. (2008) performed a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. A total of 6 SNPs within a region of strong linkage disequilibrium on 20q11.22 showed association with burning and freckling that reached genomewide significance (max odds ratio = 1.60, p = 3.9 x 10(-9)). Multipoint analysis of the area revealed an extended haplotype tagged by a 2-SNP haplotype, rs1015362G and rs4911414T, that Sulem et al. (2008) referred to as 'the ASIP haplotype.' The SNPs rs1015362 and rs4911414 lie outside the ASIP gene itself. The ASIP haplotype was significantly associated in both the Icelandic and Dutch replication samples. In the combined analysis of the discovery and replication samples, the ASIP haplotype reached genomewide significance for red hair color, freckling, and skin sensitivity to sun, in addition to burning and freckling. This pattern of association was similar to that observed for variations within MC1R associated with red hair color. The ASIP haplotype occurs on the background of the major allele of rs6058017 (600201.0001), but the correlation between the two is very weak. The strength of the association of rs6058017 with the pigmentation traits was much less than that of the ASIP haplotype, and after adjustment for rs6058017 the ASIP haplotype remained highly significant for burning and freckling (p = 1.3 x 10(-46)). After adjustment for the ASIP haplotype, the association of rs6058017 with pigmentation characteristics was only marginal (P = 0.057 for burning and freckling).
The ASIP haplotype of Sulem et al. (2008) has also been associated with susceptibility to cutaneous malignant melanoma and basal cell carcinoma (see CMM7, 612263).
Animal ModelMice that carry the lethal yellow or viable yellow mutation, 2 dominant mutations of the agouti gene on mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Klebig et al. (1995) generated transgenic mice that ectopically expressed an agouti cDNA clone encoding the normal agouti protein in all tissues examined. Transgenic mice of both sexes had yellow fur, became obese, and developed hyperinsulinemia. In addition, male transgenic mice developed hyperglycemia by 12 to 20 weeks of age. The results demonstrated that the ectopic agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, 'obese yellow' mutants.