Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 16 December 2005:
Vol. 310. no. 5755, pp. 1782 - 1786
DOI: 10.1126/science.1116238
Prev | Table of Contents | Next

Research Articles

SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans

Rebecca L. Lamason,1* Manzoor-Ali P.K. Mohideen,1{dagger} Jason R. Mest,1 Andrew C. Wong,1{ddagger} Heather L. Norton,6 Michele C. Aros,1 Michael J. Jurynec,8 Xianyun Mao,6 Vanessa R. Humphreville,1§ Jasper E. Humbert,2,9 Soniya Sinha,2 Jessica L. Moore,1|| Pudur Jagadeeswaran,10 Wei Zhao,3 Gang Ning,7 Izabela Makalowska,7 Paul M. McKeigue,11 David O'Donnell,11 Rick Kittles,12 Esteban J. Parra,13 Nancy J. Mangini,14 David J. Grunwald,8 Mark D. Shriver,6 Victor A. Canfield,4 Keith C. Cheng1,4,5

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.

1 Jake Gittlen Cancer Research Foundation, Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
2 Intercollege Graduate Degree Program in Genetics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
3 Department of Health Evaluation Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
5 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
6 Department of Anthropology, The Pennsylvania State University, University Park, PA 16802, USA.
7 The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
8 Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
9 Department of Genetics, Weis Center for Research, Danville, PA 17822, USA.
10 Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
11 Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
12 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA.
13 Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
14 Department of Anatomy and Cell Biology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USA.

* Present address: The Graduate Program in Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

{dagger} Present address: Health System Management Center, Case Western Reserve University, Cleveland, OH 44106, USA.

{ddagger} Present address: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

§ Present address: The Pennsylvania State University College of Medicine, H060, 500 University Drive, Hershey, PA 17033, USA.

|| Present address: Department of Biology, University of South Florida, Tampa, FL 33620, USA.

To whom correspondence should be addressed. E-mail: kcheng{at}psu.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Nicotine response genetics in the zebrafish.
A. M. Petzold, D. Balciunas, S. Sivasubbu, K. J. Clark, V. M. Bedell, S. E. Westcot, S. R. Myers, G. L. Moulder, M. J. Thomas, and S. C. Ekker (2009)
PNAS 106, 18662-18667
   Abstract »    Full Text »    PDF »
Singapore Genome Variation Project: A haplotype map of three Southeast Asian populations.
Y.-Y. Teo, X. Sim, R. T.H. Ong, A. K.S. Tan, J. Chen, E. Tantoso, K. S. Small, C.-S. Ku, E. J.D. Lee, M. Seielstad, et al. (2009)
Genome Res. 19, 2154-2162
   Abstract »    Full Text »    PDF »
Assessing Human Variation Data for Signatures of Natural Selection.
M. Bamshad and J. C. Stephens (2009)
CSH Protocols 2009, pdb.top61
   Abstract »    Full Text »
Genome-wide comparisons of variation in linkage disequilibrium.
Y. Y. Teo, A. E. Fry, K. Bhattacharya, K. S. Small, D. P. Kwiatkowski, and T. G. Clark (2009)
Genome Res. 19, 1849-1860
   Abstract »    Full Text »    PDF »
Sodium\#8211;calcium exchangers contribute to the regulation of cytosolic calcium levels in mouse taste cells.
A. I. Laskowski and K. F. Medler (2009)
J. Physiol. 587, 4077-4089
   Abstract »    Full Text »    PDF »
K+-dependent Na+/Ca2+ exchanger 3 is involved in renal active calcium transport and is differentially expressed in the mouse kidney.
G.-S. Lee, K.-C. Choi, and E.-B. Jeung (2009)
Am J Physiol Renal Physiol 297, F371-F379
   Abstract »    Full Text »    PDF »
{alpha}MSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism.
Y. Cheli, F. Luciani, M. Khaled, L. Beuret, K. Bille, P. Gounon, J.-P. Ortonne, C. Bertolotto, and R. Ballotti (2009)
J. Biol. Chem. 284, 18699-18706
   Abstract »    Full Text »    PDF »
Nonsense-Mediated mRNA Decay Effectors Are Essential for Zebrafish Embryonic Development and Survival.
N. Wittkopp, E. Huntzinger, C. Weiler, J. Sauliere, S. Schmidt, M. Sonawane, and E. Izaurralde (2009)
Mol. Cell. Biol. 29, 3517-3528
   Abstract »    Full Text »    PDF »
Mapping of the Domestic Cat "SILVER" Coat Color Locus Identifies a Unique Genomic Location for Silver in Mammals.
M. Menotti-Raymond, V. A. David, E. Eizirik, M. E. Roelke, H. Ghaffari, and S. J. O'Brien (2009)
J. Hered. 100, S8-S13
   Abstract »    Full Text »    PDF »
Constructing genomic maps of positive selection in humans: Where do we go from here?.
J. M. Akey (2009)
Genome Res. 19, 711-722
   Abstract »    Full Text »    PDF »
Signals of recent positive selection in a worldwide sample of human populations.
J. K. Pickrell, G. Coop, J. Novembre, S. Kudaravalli, J. Z. Li, D. Absher, B. S. Srinivasan, G. S. Barsh, R. M. Myers, M. W. Feldman, et al. (2009)
Genome Res. 19, 826-837
   Abstract »    Full Text »    PDF »
Molecular genetics of human pigmentation diversity.
R. A. Sturm (2009)
Hum. Mol. Genet. 18, R9-R17
   Abstract »    Full Text »    PDF »
Modification of the Association Between Serotonin Transporter Genotype and Risk of Posttraumatic Stress Disorder in Adults by County-Level Social Environment.
K. C. Koenen, A. E. Aiello, E. Bakshis, A. B. Amstadter, K. J. Ruggiero, R. Acierno, D. G. Kilpatrick, J. Gelernter, and S. Galea (2009)
Am. J. Epidemiol. 169, 704-711
   Abstract »    Full Text »    PDF »
Birth Prevalence and Mutation Spectrum in Danish Patients with Autosomal Recessive Albinism.
K. Gronskov, J. Ek, A. Sand, R. Scheller, A. Bygum, K. Brixen, K. Brondum-Nielsen, and T. Rosenberg (2009)
Invest. Ophthalmol. Vis. Sci. 50, 1058-1064
   Abstract »    Full Text »    PDF »
Gene Expression Levels Are a Target of Recent Natural Selection in the Human Genome.
S. Kudaravalli, J.-B. Veyrieras, B. E. Stranger, E. T. Dermitzakis, and J. K. Pritchard (2009)
Mol. Biol. Evol. 26, 649-658
   Abstract »    Full Text »    PDF »
Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r.
E. Le Pape, T. Passeron, A. Giubellino, J. C. Valencia, R. Wolber, and V. J. Hearing (2009)
PNAS 106, 1802-1807
   Abstract »    Full Text »    PDF »
Emerging gene knockout technology in zebrafish: zinc-finger nucleases.
S. L. Amacher (2008)
Brief Funct Genomic Proteomic 7, 460-464
   Abstract »    Full Text »    PDF »
Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation.
E. H. Budi, L. B. Patterson, and D. M. Parichy (2008)
Development 135, 2603-2614
   Abstract »    Full Text »    PDF »
Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation.
Y. Suzuki, A. Pasch, O. Bonny, M. G. Mohaupt, M. A. Hediger, and F. J. Frey (2008)
Hum. Mol. Genet. 17, 1613-1618
   Abstract »    Full Text »    PDF »
A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness.
A. Fujimoto, R. Kimura, J. Ohashi, K. Omi, R. Yuliwulandari, L. Batubara, M. S. Mustofa, U. Samakkarn, W. Settheetham-Ishida, T. Ishida, et al. (2008)
Hum. Mol. Genet. 17, 835-843
   Abstract »    Full Text »    PDF »
Ocular Albinism and Hypopigmentation Defects in Slc24a5-/- Mice.
P. Vogel, R. W. Read, R. B. Vance, K. A. Platt, K. Troughton, and D. S. Rice (2008)
Vet. Pathol. 45, 264-279
   Abstract »    Full Text »    PDF »
SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis.
R. S. Ginger, S. E. Askew, R. M. Ogborne, S. Wilson, D. Ferdinando, T. Dadd, A. M. Smith, S. Kazi, R. T. Szerencsei, R. J. Winkfein, et al. (2008)
J. Biol. Chem. 283, 5486-5495
   Abstract »    Full Text »    PDF »
A Critical Role for the Potassium-Dependent Sodium-Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage.
O. Cuomo, R. Gala, G. Pignataro, F. Boscia, A. Secondo, A. Scorziello, A. Pannaccione, D. Viggiano, A. Adornetto, P. Molinaro, et al. (2008)
J. Neurosci. 28, 2053-2063
   Abstract »    Full Text »    PDF »
Characterization of Japanese Quail yellow as a Genomic Deletion Upstream of the Avian Homolog of the Mammalian ASIP (agouti) Gene.
N. J. Nadeau, F. Minvielle, S. Ito, M. Inoue-Murayama, D. Gourichon, S. A. Follett, T. Burke, and N. I. Mundy (2008)
Genetics 178, 777-786
   Abstract »    Full Text »    PDF »
The Serotonin Transporter Genotype and Social Support and Moderation of Posttraumatic Stress Disorder and Depression in Hurricane-Exposed Adults.
D. G. Kilpatrick, K. C. Koenen, K. J. Ruggiero, R. Acierno, S. Galea, H. S. Resnick, J. Roitzsch, J. Boyle, and J. Gelernter (2007)
Am J Psychiatry 164, 1693-1699
   Abstract »    Full Text »    PDF »
AssociationDB: web-based exploration of genomic association.
D. Seelow, K. Hoffmann, and T. H. Lindner (2007)
Bioinformatics 23, 2643-2644
   Abstract »    Full Text »    PDF »
K+-Dependent Na+/Ca2+ Exchangers: Key Contributors to Ca2+ Signaling.
F. Visser and J. Lytton (2007)
Physiology 22, 185-192
   Abstract »    Full Text »    PDF »
Manipulating Mitotic Recombination in the Zebrafish Embryo Through RecQ Helicases.
J. Xie, S. L. Bessling, T. K. Cooper, H. C. Dietz, A. S. McCallion, and S. Fisher (2007)
Genetics 176, 1339-1342
   Abstract »    Full Text »    PDF »
Genetic Evidence for the Convergent Evolution of Light Skin in Europeans and East Asians.
H. L. Norton, R. A. Kittles, E. Parra, P. McKeigue, X. Mao, K. Cheng, V. A. Canfield, D. G. Bradley, B. McEvoy, and M. D. Shriver (2007)
Mol. Biol. Evol. 24, 710-722
   Abstract »    Full Text »    PDF »
Analysis of Ion Interactions with the K+ -dependent Na+/Ca+ Exchangers NCKX2, NCKX3, and NCKX4: IDENTIFICATION OF THR-551 AS A KEY RESIDUE IN DEFINING THE APPARENT K+ AFFINITY OF NCKX2.
F. Visser, V. Valsecchi, L. Annunziato, and J. Lytton (2007)
J. Biol. Chem. 282, 4453-4462
   Abstract »    Full Text »    PDF »
Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2.
H. F. Altimimi and P. P. M. Schnetkamp (2007)
J. Biol. Chem. 282, 3720-3729
   Abstract »    Full Text »    PDF »
The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model.
B. McEvoy, S. Beleza, and M. D. Shriver (2006)
Hum. Mol. Genet. 15, R176-R181
   Abstract »    Full Text »    PDF »
Zebrafish Genomic Instability Mutants and Cancer Susceptibility.
J. L. Moore, L. M. Rush, C. Breneman, M.-A. P. K. Mohideen, and K. C. Cheng (2006)
Genetics 174, 585-600
   Abstract »    Full Text »    PDF »
Heterozygosity for a POMC-Null Mutation and Increased Obesity Risk in Humans.
I. S. Farooqi, S. Drop, A. Clements, J. M. Keogh, J. Biernacka, S. Lowenbein, B. G. Challis, and S. O'Rahilly (2006)
Diabetes 55, 2549-2553
   Abstract »    Full Text »    PDF »
Novel role for K+-dependent Na+/Ca2+ exchangers in regulation of cytoplasmic free Ca2+ and contractility in arterial smooth muscle.
H. Dong, Y. Jiang, C. R. Triggle, X. Li, and J. Lytton (2006)
Am J Physiol Heart Circ Physiol 291, H1226-H1235
   Abstract »    Full Text »    PDF »
A Scan for Signatures of Positive Selection in Candidate Loci for Skin Pigmentation in Humans.
N. Izagirre, I. Garcia, C. Junquera, C. de la Rua, and S. Alonso (2006)
Mol. Biol. Evol. 23, 1697-1706
   Abstract »    Full Text »    PDF »
Malignant melanoma: genetics and therapeutics in the genomic era..
L. Chin, L. A. Garraway, and D. E. Fisher (2006)
Genes & Dev. 20, 2149-2182
   Abstract »    Full Text »    PDF »
Genetic variants and common diseases--better late than never..
S. O'Rahilly and N. J. Wareham (2006)
N. Engl. J. Med. 355, 306-308
   Full Text »    PDF »
Positive natural selection in the human lineage..
P. C. Sabeti, S. F. Schaffner, B. Fry, J. Lohmueller, P. Varilly, O. Shamovsky, A. Palma, T. S. Mikkelsen, D. Altshuler, and E. S. Lander (2006)
Science 312, 1614-1620
   Abstract »    Full Text »    PDF »
About Face: Forensic Genetic Testing for Race and Visible Traits.
P. N. Ossorio (2006)
J. Law Med. Ethics 34, 277-292
   PDF »
Highlights From The Literature.
(2006)
Physiology 21, 83-85
   Full Text »    PDF »
Fishing for New Pigment Genes.
(2006)
Journal Watch Dermatology 2006, 3
   Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)