The fifth member of the potassium-dependent sodium calcium exchanger (NCKX) family, SLC24A5, was recently found to be critical for normal pigmentation in zebrafish melanophores and retinal pigmented epithelium through the cloning of the golden locus (1). Independently, as part of a whole genome scan in a population with ancestry from the Indian sub-continent, we have identified 2 single nucleotide polymorphisms (SNPs) that are strongly associated with natural variation in human skin colour. Genotype analysis revealed that the ancestral allele (A111) of a non-synonymous SNP in SLC24A5 (pA111T, rs1426654) is highly associated with dark skin (allele frequency difference = 38.7%; alternative allele freq = 49.13% in dark subjects compared with 10.43% in light subjects). Together with data from the human HapMap (2) and African-American and African-Caribbean populations (1) our results indicate that SLC24A5 plays a key role in human skin pigmentation. SLC24A5 was the predominant SLC24 transcript detected in human skin biopsies and cultured primary human melanocytes by real-time PCR. Immuno-localisation using affinity purified anti-NCKX5 peptide antibodies suggest that the antibody recognises an intracellular epitope in cultured melanocytes, confirmed using siRNA-mediated knockdown of NCKX5 protein. The nsSNP (pA111T) lies in a region of NCKX5 amino acid sequence that is highly conserved between different NCKX family members. Site-directed mutagenesis studies on a heterologously expressed NCKX2 with the 177T SNP demonstrated that the light skin variant has reduced ion exchange function compared to the A177 SNP, with no significant variation in ion dependencies. These data suggest that SLC24A5-mediated ion exchange may affect skin pigmentation, but the mechanism remains to be elucidated.
Life Sciences 2007 (2007) Proc Life Sciences, PC173
Poster Communications: Sodium-calcium exchange in human skin pigmentation
R. M. Ogborne1, T. Dadd1, A. Fereday1, W. Filsell1, R. S. Ginger1, C. Jarman1, S. Wilson1, J. Pople1, D. Ferdinando1, S. Kazi1, S. Askew1</s
1. Corporate Research, Unilever R&D, Sharnbrook, Bedfordshire, United Kingdom. 2. Perlegen Sciences Inc, Mountain View, CA, USA. 3. University of Calgary, Calgary, AB, Canada.
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