SLC24A5
| Solute carrier family 24, member 5 | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | SLC24A5; JSX; NCKX5; SHEP4 | ||||||||||||
| External IDs | OMIM: 609802 MGI: 2677271 HomoloGene: 18400 GeneCards: SLC24A5 Gene | ||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 283652 | 317750 | |||||||||||
| Ensembl | ENSG00000188467 | ENSMUSG00000035183 | |||||||||||
| UniProt | Q71RS6 | Q8C261 | |||||||||||
| RefSeq (mRNA) | NM_205850 | NM_175034.3 | |||||||||||
| RefSeq (protein) | NP_995322 | NP_778199.2 | |||||||||||
| Location (UCSC) | Chr 15: 48.41 – 48.43 Mb |
Chr 2: 124.89 – 124.91 Mb |
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| PubMed search | [1] | [2] | |||||||||||
Sodium/potassium/calcium exchanger 5 (NCKX5) also known as solute carrier family 24 member 5 (SLC24A5) is a protein that in humans is encoded by the SLC24A5 gene that has a major influence on natural skin colour variation.[1] The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger family. Sequence variation in the SLC24A5 gene, particularly a non-synomyous SNP changing the amino acid at position 111 in NCKX5 from alanine to threonine, has been associated with differences in skin pigmentation.[2]
Contents |
[edit] Gene
The SLC24A5 gene, in humans, is located on the long (q) arm of chromosome 15 on position 21.1, from base pair 46,200,461 to base pair 46,221,881.[1]
[edit] Protein
NCKX5 is 43 kDa protein that is partially localized to the trans-Golgi network in melanocytes. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in melanin pigment production. Site-directed mutagenesis corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity.[2]
[edit] Effect on skin color
SLC24A5 appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. In this work, cancer geneticist Keith Cheng used electron microscopy to probe the cellular mechanism underlying the lighter color of golden zebrafish, and noted a striking similarity between the changes of melanocytes (pigment cells) in those lighter-skinned fish and lighter-skinned humans (in particular, Europeans). This led Cheng to ask his Pennsylvania State University colleague, anthropologist Mark D. Shriver, whether he had human DNA linked to skin color measurements. Shriver, who collaborates internationally to study the basis of variation in human skin color and other features in human populations, pointed to the then-new International HapMap Project database of genetic variation in human populations, and found that the gene has a single "coding" polymorphism - one that changes an amino acid. The two primary alleles differ in only one nucleotide, changing the 111th amino acid from alanine to threonine, abbreviated "A111T".[1][3][4]
The threonine allele was present in 98.7 to 100% among several European samples, while the alanine form was found in 93 to 100% of samples of Africans, East Asians and Indigenous Americans. The variation is a SNP polymorphism rs1426654, which had been previously shown to be second among 3011 tabulated SNPs ranked as ancestry-informative markers. Collaborator Victor Canfield plotted the human data to estimate that this single change in SLC24A5 explains between 25 and 38% of the difference in skin melanin index between peoples of West African vs. European Ancestry.
The discovery of this gene has interesting social implications because the "derived" European allele was derived by mutation from the ancestral gene sequence. As noted by Penn State's Victor Canfield, the ancestral alanine is conserved in all vertebrates sequenced to date, mutant only in the European allele, but only rarely in West African or East Asian (primarily Chinese, Japanese and Korean) populations (presumably by admixture). Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the A111T mutation may be the subject of the single largest degree of selection in human populations of European ancestry. Selection for the derived allele is based on the need for sunlight to produce the essential nutrient, vitamin D. In northerly latitudes, there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin necessary for survival. Tests for this variation has obvious application to forensic science.
It has been estimated that the threonine allele became predominant amongst Europeans 5,300 to 6,000 years ago [5].
[edit] See also
[edit] References
- ^ a b c Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC (December 2005). "SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans". Science 310 (5755): 1782–6. doi:10.1126/science.1116238. PMID 16357253.
- ^ a b Ginger RS, Askew SE, Ogborne RM, Wilson S, Ferdinando D, Dadd T, Smith AM, Kazi S, Szerencsei RT, Winkfein RJ, Schnetkamp PP, Green MR (February 2008). "SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis". J. Biol. Chem. 283 (9): 5486–95. doi:10.1074/jbc.M707521200. PMID 18166528.
- ^ "Key gene 'controls skin colour'". Health. BBC News. 2005-12-16. http://news.bbc.co.uk/2/hi/health/4531966.stm. Retrieved 2010-10-23.
- ^ "Fish gene sheds light on human skin color variation". Penn State Live. Penn State University. 2005-12-16. http://live.psu.edu/story/15166. Retrieved 2010-10-23.
- ^ Gibbons A (April 2007). "American Association of Physical Anthropologists meeting. European skin turned pale only recently, gene suggests". Science 316 (5823): 364. doi:10.1126/science.316.5823.364a. PMID 17446367. http://galsatia.files.wordpress.com/2007/04/blanche_paleur.pdf.
[edit] Further reading
- Grønskov K, Ek J, Sand A, et al. (2009). "Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism.". Invest. Ophthalmol. Vis. Sci. 50 (3): 1058–64. doi:10.1167/iovs.08-2639. PMID 19060277.
- Cook AL, Chen W, Thurber AE, et al. (2009). "Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci.". J. Invest. Dermatol. 129 (2): 392–405. doi:10.1038/jid.2008.211. PMID 18650849.
- Nan H, Kraft P, Hunter DJ, Han J (2009). "Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians.". Int. J. Cancer 125 (4): 909–17. doi:10.1002/ijc.24327. PMC 2700213. PMID 19384953. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2700213.
- Meda SA, Jagannathan K, Gelernter J, et al. (2009). "A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia.". NeuroImage 53 (3): HASH(0x24e4bb0). doi:10.1016/j.neuroimage.2009.11.052. PMID 19944766.
- Stokowski RP, Pant PV, Dadd T, et al. (2007). "A genomewide association study of skin pigmentation in a South Asian population.". Am. J. Hum. Genet. 81 (6): 1119–32. doi:10.1086/522235. PMC 2276347. PMID 17999355. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2276347.
- Dagle JM, Lepp NT, Cooper ME, et al. (2009). "Determination of genetic predisposition to patent ductus arteriosus in preterm infants.". Pediatrics 123 (4): 1116–23. doi:10.1542/peds.2008-0313. PMC 2734952. PMID 19336370. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2734952.
- Sulem P, Gudbjartsson DF, Stacey SN, et al. (2007). "Genetic determinants of hair, eye and skin pigmentation in Europeans.". Nat. Genet. 39 (12): 1443–52. doi:10.1038/ng.2007.13. PMID 17952075.
- Cai X, Lytton J (2004). "Molecular cloning of a sixth member of the K+-dependent Na+/Ca2+ exchanger gene family, NCKX6.". J. Biol. Chem. 279 (7): 5867–76. doi:10.1074/jbc.M310908200. PMID 14625281.
- Chi A, Valencia JC, Hu ZZ, et al. (2006). "Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.". J. Proteome Res. 5 (11): 3135–44. doi:10.1021/pr060363j. PMID 17081065.
- Soejima M, Koda Y (2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2.". Int. J. Legal Med. 121 (1): 36–9. doi:10.1007/s00414-006-0112-z. PMID 16847698.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
- Dimisianos G, Stefanaki I, Nicolaou V, et al. (2009). "A study of a single variant allele (rs1426654) of the pigmentation-related gene SLC24A5 in Greek subjects.". Exp. Dermatol. 18 (2): 175–7. doi:10.1111/j.1600-0625.2008.00758.x. PMID 18637132.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
