SLC24A5

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Solute carrier family 24 (sodium/potassium/calcium exchanger), member 5
Identifiers
Symbols SLC24A5 ; JSX; NCKX5; OCA6; SHEP4
External IDs OMIM609802 MGI2677271 HomoloGene18400 IUPHAR: 1049 GeneCards: SLC24A5 Gene
Orthologs
Species Human Mouse
Entrez 283652 317750
Ensembl ENSG00000188467 ENSMUSG00000035183
UniProt Q71RS6 Q8C261
RefSeq (mRNA) NM_205850 NM_175034
RefSeq (protein) NP_995322 NP_778199
Location (UCSC) Chr 15:
48.12 – 48.14 Mb
Chr 2:
125.07 – 125.09 Mb
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-synonymous SNP changing the amino acid at position 111 in NCKX5 from alanine to threonine, has been associated with differences in skin pigmentation.[2]

The SLC24A5 gene's derived threonine or Ala111Thr allele (rs1426654[3]) has been shown to be a major factor in the light skin tone of Europeans compared to Africans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and West Africans.[1][4] It has been the subject of recent selection in Western Eurasia, and is fixed in European populations.[5][6][7]

Gene[edit]

Location of the SLC24A5 gene in human chromosome 15.

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]

Protein[edit]

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]

Effect on skin color[edit]

Global frequency distribution of the SLC24A5 gene's ancestral Ala111 allele (yellow) and its derived Ala111Thr allele (blue).

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. Evidence in the International HapMap Project database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary alleles differing by only one nucleotide, changing the 111th amino acid from alanine to threonine, abbreviated "A111T".[1][8][9]

The derived threonine allele (Ala111Thr; also known as A111T or Thr111) represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in 93 to 100% of samples of Sub-Saharan 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. 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.

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.[1] It is theorised that selection for the derived allele is based on the need for sunlight to produce the essential nutrient vitamin D. In northerly latitudes, where there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin more suitable for survival.[10] Tests for this variation have obvious application to forensic science.

It has been estimated that the threonine allele became predominant among Europeans 11,000 to 19,000 years ago.[4][5]

See also[edit]

References[edit]

  1. ^ a b c d e 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 (Dec 2005). "SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans". Science 310 (5755): 1782–6. doi:10.1126/science.1116238. PMID 16357253. 
  2. ^ 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 (Feb 2008). "SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis". The Journal of Biological Chemistry 283 (9): 5486–95. doi:10.1074/jbc.M707521200. PMID 18166528. 
  3. ^ Reference SNP(refSNP) Cluster Report: rs1426654 **clinically associated**. Ncbi.nlm.nih.gov (2008-12-30). Retrieved on 2011-02-27.
  4. ^ a b Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD (Mar 2007). "Genetic evidence for the convergent evolution of light skin in Europeans and East Asians". Molecular Biology and Evolution 24 (3): 710–22. doi:10.1093/molbev/msl203. PMID 17182896. Lay summaryScience Magazine. 
  5. ^ a b Beleza S, Santos AM, McEvoy B, Alves I, Martinho C, Cameron E, Shriver MD, Parra EJ, Rocha J (Jan 2013). "The timing of pigmentation lightening in Europeans". Molecular Biology and Evolution 30 (1): 24–35. doi:10.1093/molbev/mss207. PMC 3525146. PMID 22923467. 
  6. ^ Soejima M, Koda Y (Jan 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine 121 (1): 36–9. doi:10.1007/s00414-006-0112-z. PMID 16847698. 
  7. ^ Ang KC, Ngu MS, Reid KP, Teh MS, Aida ZS, Koh DX, Berg A, Oppenheimer S, Salleh H, Clyde MM, Md-Zain BM, Canfield VA, Cheng KC (2012). Kivisild T, ed. "Skin color variation in Orang Asli tribes of Peninsular Malaysia". PloS One 7 (8): e42752. doi:10.1371/journal.pone.0042752. PMC 3418284. PMID 22912732. 
  8. ^ "Key gene 'controls skin colour'". Health. BBC News. 2005-12-16. Retrieved 2010-10-23. 
  9. ^ "Fish gene sheds light on human skin color variation". Penn State Live. Penn State University. 2005-12-16. Retrieved 2010-10-23. 
  10. ^ Jablonski NG, Chaplin G (Jul 2000). "The evolution of human skin coloration" (PDF). Journal of Human Evolution 39 (1): 57–106. doi:10.1006/jhev.2000.0403. PMID 10896812. 

Further reading[edit]

  • Grønskov K, Ek J, Sand A, Scheller R, Bygum A, Brixen K, Brondum-Nielsen K, Rosenberg T (Mar 2009). "Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism". Investigative Ophthalmology & Visual Science 50 (3): 1058–64. doi:10.1167/iovs.08-2639. PMID 19060277. 
  • Cook AL, Chen W, Thurber AE, Smit DJ, Smith AG, Bladen TG, Brown DL, Duffy DL, Pastorino L, Bianchi-Scarra G, Leonard JH, Stow JL, Sturm RA (Feb 2009). "Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci". The Journal of Investigative Dermatology 129 (2): 392–405. doi:10.1038/jid.2008.211. PMID 18650849. 
  • Nan H, Kraft P, Hunter DJ, Han J (Aug 2009). "Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians". International Journal of Cancer. Journal International Du Cancer 125 (4): 909–17. doi:10.1002/ijc.24327. PMC 2700213. PMID 19384953. 
  • Meda SA, Jagannathan K, Gelernter J, Calhoun VD, Liu J, Stevens MC, Pearlson GD (Nov 2010). "A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia". NeuroImage 53 (3): 1007–15. doi:10.1016/j.neuroimage.2009.11.052. PMID 19944766. 
  • Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR (Dec 2007). "A genomewide association study of skin pigmentation in a South Asian population". American Journal of Human Genetics 81 (6): 1119–32. doi:10.1086/522235. PMC 2276347. PMID 17999355. 
  • Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC (Apr 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. 
  • Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Pálsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (Dec 2007). "Genetic determinants of hair, eye and skin pigmentation in Europeans". Nature Genetics 39 (12): 1443–52. doi:10.1038/ng.2007.13. PMID 17952075. 
  • Cai X, Lytton J (Feb 2004). "Molecular cloning of a sixth member of the K+-dependent Na+/Ca2+ exchanger gene family, NCKX6". The Journal of Biological Chemistry 279 (7): 5867–76. doi:10.1074/jbc.M310908200. PMID 14625281. 
  • Chi A, Valencia JC, Hu ZZ, Watabe H, Yamaguchi H, Mangini NJ, Huang H, Canfield VA, Cheng KC, Yang F, Abe R, Yamagishi S, Shabanowitz J, Hearing VJ, Wu C, Appella E, Hunt DF (Nov 2006). "Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes". Journal of Proteome Research 5 (11): 3135–44. doi:10.1021/pr060363j. PMID 17081065. 
  • Soejima M, Koda Y (Jan 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine 121 (1): 36–9. doi:10.1007/s00414-006-0112-z. PMID 16847698. 
  • Dimisianos G, Stefanaki I, Nicolaou V, Sypsa V, Antoniou C, Poulou M, Papadopoulos O, Gogas H, Kanavakis E, Nicolaidou E, Katsambas AD, Stratigos AJ (Feb 2009). "A study of a single variant allele (rs1426654) of the pigmentation-related gene SLC24A5 in Greek subjects". Experimental Dermatology 18 (2): 175–7. doi:10.1111/j.1600-0625.2008.00758.x. PMID 18637132. 

External links[edit]