Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians

Abstract

Human melanocortin 1 receptor (MC1R) is a seven transmembrane G-coupled protein receptor that upregulates the cAMP pathway. Several functional variants of MC1R that show an impaired ability to activate the cAMP pathway are strongly associated with fair skin and red hair in Europeans and European descendants. The sequence variations of the MC1R gene were repeatedly investigated against worldwide populations; however, there was no evidence that functional variant of MC1R exists in non-European descendants. We report the presence of novel functional variants of MC1R with Asian origins. Three novel variants of MC1R, Phe147Delta, Thr157Ile, and Pro159Thr, were identified in our screening for the sequence variations of the MC1R gene against 995 individuals from 30 Asian and Oceanian populations; there was a single case for the Pro159Thr variant allele and two instances of Phe147Delta and Thr157Ile variant alleles. Our pharmacological assay revealed that Phe147Delta, Thr157Ile, and Pro159Thr variant showed similar or more dramatically impaired activities in comparison with Arg151Cys, which is a major functional variant of MC1R in Europeans. These functional variant alleles were geographically localized in relatively high latitudes, which suggest that the adaptation to ambient UV light intensity may play an important role in shaping the geographical distribution of MC1R alleles in Asia and Oceania.

Association of melanocortin 1 receptor gene (MC1R) polymorphisms with skin reflectance and freckles in Japanese

“…However, an in vitro study showed that the 92M allele caused impaired MC1R function; in contrast, the 163Q allele had almost the same response to a-melanocyte simulation hormone as the human consensus allele. 32 These results may explain the difference in the effect of the V92M and R163Q alleles on skin pigmentation.…”

“…An in vitro study on the function of MC1R variants also indicates that 163Q functions normally when compared with the consensus. 32 Motokawa et al 68 investigated polymorphisms in the promoter region of MC1R linked to R163Q among 247 Japanese. They found that the promoter haplotypes with a combination of À490T, À445A and À226T, 98.5% of which bore the 163Q allele in the coding region, showed lower OR for initiating freckles and solar lentigines than did the human consensus haplotype ( À490C, À445G, À226A).…”

“…31 In Asian populations, more than 10 variants have been reported, of which the V92M and R163Q variants are observed at high frequencies relative to the frequencies observed in non-Asian populations. [32][33][34] Recent genome scans for selective sweeps have revealed that strong positive selection has acted on pigmentationrelated genes. [35][36][37] Coop et al 38 suggested a signature of an 'East Asian sweep' on R163Q (rs885479) based on F ST and XP-EHH in genome-wide single-nucleotide polymorphism (SNP) data from the HapMap, the CEPH-Human Genome Diversity Panel and Perlegen data set.…”

Colorful DNA polymorphisms in humans

“…MC1R is a very small gene of less than 1 kb in size, which lacks any introns, thus being attractive for direct DNA sequencing to unveil pigmentation associated or causing DNA variants. Non-synonymous variants in MC1R were found to be nearly absent in Africans but highly enriched in Europeans and Asians [105][106][107][108]. Nine DNA variants, V60L (rs1805005), D84E (rs1805006), R151C (rs1805007), I155T (rs1110440), R160W (rs1805008), R163Q (rs885479), R142H (rs11547464), D294H (rs1805009), and V92M (rs2228479), are common in Europeans, and two DNA variants, A163G and V92M, are common in Asians [106,109].…”

MC1R gene variants involvement in human OCA phenotype

“…The study of RHC MC1R variants provided information about their association with other phenotypes and their effect on functioning of MSH-R has extended its role beyond pigmentation to diseased phenotypes. The MC1R variants, mainly the RHC alleles were also reported to be associated with increased risk of various types of melanoma [41] and UV induced susceptibility to skin damage [42]. The MC1R variants have been reported to be associated with pigmentary disorders including vitiligo [43], severe photoaging [44], congenital melanocytic nevi [45] and OCA [46].…”