To examine the rs1426654 polymorphism in a sample of Greek patients with minor cutaneous disease and investigate a potential interaction of SLC24A5 gene with MC1R in the phenotypic expression of skin colour.

Ayungo, Melanie : 13/08/03

Introduction

Skin pigmentation varies significantly within and among human populations possibly as a result of localized adaptation to different UVR conditions

Genes such as melanocortin receptor-1 gene (MC1R), have been associated both with a specific pigmentary phenotype and an increased likelihood of melanoma and skin cancer

Recently, the cloning of a zebrafish mutant, golden, identified slc24a5 as a gene involved in fish skin pigmentation

Correspondingly, its human orthologue, SLC24A5, has been recognized as a major contributing locus underlying human skin pigmentation.

An allelic variant of this gene (rs1426654) that substitutes a fully conserved alanine with threonine at position 111 is found almost ubiquitously in Western European populations but rarely in dark-skinned non-European populations.

The MC1R gene

•provides instructions for making a protein called the melanocortin 1 receptor. •important role in normal pigmentation•located on the surface of melanocytes•melanocortin 1 receptor controls which type of melanin is produced by melanocytes.•When the receptor is activated, it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin.•Common variations (polymorphisms) in the MC1R gene are associated with normal differences in skin and hair color. •Certain genetic variations are most common in people with red hair, fair skin, freckles, and an increased sensitivity to sun exposure. •These MC1R polymorphisms reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production, causing melanocytes to make mostly pheomelanin.

Cation exchanger involved in pigmentation, possibly by participating in ion transport in melanosomes. Probably transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).

An alteration in the normal sequence of a gene, the significance of which is often unclear until further study of the genotype and corresponding phenotype occurs in a sufficiently large population.

Complete gene sequencing often identifies numerous allelic variants (sometimes hundreds) for a given gene.

A gene that has remained essentially unchanged throughout evolution. Conservation of a gene indicates that it is unique and essential: There is not an extra copy of that gene with which evolution can tinker, and changes in the gene are likely to be lethal.

Experimental Method1. The study included 158 Caucasian subjects (outpatients with minor skin problems (70%) and medical personnel (30%) seen at the outpatient dermatology service of

A. Sygros Hospital in Athens)

Standardized interview regarding residential history, medical history,

Personal or family history of cancer exposure to solar and artificial UVR.

Skin phototype according to the Fitzpatrick classification, and skin, hair and eye colour based on a standardized colour system.

2. 200 μl of whole blood.

Genomic DNA

3. For the determination of the rs1426654 polymorphism in exon 3 of the SLC24A5 gene, an allele-specific

PCR assay was designed.

4. The detection of MC1R variants was performed

by sequencing analysis

Table 1.  Demographic and phenotypic characteristics of 158 study subjects

The demographic and phenotypical characteristics in the study group The vast majority of subjects (99%) carried the Thr111/Thr111 allele. No subject with homozygosity for Ala111 was identified. Only two samples displayed heterozygosity for the alanine and threonine allele. The prevalence of heterozygosity was 1.26% (95% CI: 0.15%–4.50%) among studied

subjects (P = 0.940). The allele frequency of the Ala111 allele was 0.00623, while that of Thr111 was 0.993. The phenotypic characteristics and genotype data with regard to MC1R of subjects with

the Ala111 polymorphism are depicted in Table 2. One case had a phototype III with light brown skin coloration, and another case had fair (white skin) and phototype II. Both subjects with Thr111/Ala111 genotype carried a MC1R polymorphism (V92M and V60L, respectively).

Result

Conclusion

In conclusion, our results confirmed previous studies showing a fixation of the Thr111/Thr111 haplotype in Europeans, even in those with a darker skin complexion or skin phototype III/IV.

In contrast to other pigmentation genes, such as MC1R, which regulates subtle changes of pigmentary phenotype within the white population, the SLC24A5 gene is more likely to be responsible for gross differences in skin pigmentation among populations.