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      Allelic Heterogeneity at the Equine KIT Locus in Dominant White ( W) Horses

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          Abstract

          White coat color has been a highly valued trait in horses for at least 2,000 years. Dominant white ( W) is one of several known depigmentation phenotypes in horses. It shows considerable phenotypic variation, ranging from ∼50% depigmented areas up to a completely white coat. In the horse, the four depigmentation phenotypes roan, sabino, tobiano, and dominant white were independently mapped to a chromosomal region on ECA 3 harboring the KIT gene. KIT plays an important role in melanoblast survival during embryonic development. We determined the sequence and genomic organization of the ∼82 kb equine KIT gene. A mutation analysis of all 21 KIT exons in white Franches-Montagnes Horses revealed a nonsense mutation in exon 15 (c.2151C>G, p.Y717X). We analyzed the KIT exons in horses characterized as dominant white from other populations and found three additional candidate causative mutations. Three almost completely white Arabians carried a different nonsense mutation in exon 4 (c.706A>T, p.K236X). Six Camarillo White Horses had a missense mutation in exon 12 (c.1805C>T, p.A602V), and five white Thoroughbreds had yet another missense mutation in exon 13 (c.1960G>A, p.G654R). Our results indicate that the dominant white color in Franches-Montagnes Horses is caused by a nonsense mutation in the KIT gene and that multiple independent mutations within this gene appear to be responsible for dominant white in several other modern horse populations.

          Author Summary

          White horses have always been highly valued by their human owners. Their important role in history is reflected by their widespread use as heraldic animals (e.g., on the flags of the German states of Lower Saxony and North Rhine-Westphalia). In the Swiss Franches-Montagnes Horse population, a completely white mare named Cigale was born out of solid brown parents in 1957. The white phenotype is inherited as an autosomal dominant trait and all living white Franches-Montagnes Horses are descendants of Cigale. We sequenced the KIT gene in white and solid-colored Franches-Montagnes Horses and found a mutation that inactivates the gene product and thus leads to a lack of pigment-forming cells in the skin of white horses. We then analyzed white horses from other populations and found three additional independent candidate causative mutations in white Thoroughbreds, Arabians, and Camarillo White Horses. The research thus revealed independent mutation events leading to white coat color in different horse populations. Our findings will allow genetic testing and a more precise classification of horses with white coat color.

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          Most cited references23

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          Signal transduction via the stem cell factor receptor/c-Kit.

          Together with its ligand, stem cell factor, the receptor tyrosine kinase c-Kit is a key controlling receptor for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Stimulation of c-Kit by its ligand leads to dimerization of receptors, activation of its intrinsic tyrosine kinase activity and phosphorylation of key tyrosine residues within the receptor. These phosphorylated tyrosine residues serve as docking sites for a number of signal transduction molecules containing Src homology 2 domains, which will thereby be recruited to the receptor and activated many times through phosphorylation by the receptor. This review discusses our current knowledge of signal transduction molecules and signal transduction pathways activated by c-Kit and how their activation can be connected to the physiological outcome of c-Kit signaling.
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            Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor.

            Signaling by stem cell factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-cell lymphomas. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cgamma, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control alphaC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites.
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              Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.

              Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                plge
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                November 2007
                9 November 2007
                26 September 2007
                : 3
                : 11
                : e195
                Affiliations
                [1 ] Institute of Genetics, Vetsuisse Faculty, University of Berne, Berne, Switzerland
                [2 ] DermFocus, Vetsuisse Faculty, University of Berne, Berne, Switzerland
                [3 ] M. H. Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, United States of America
                [4 ] Institute of Prehistory and Archaeological Sciences, University of Basel, Basel, Switzerland
                [5 ] Department of Genetics, University of Cordoba, Gregory Mendel Building, Cordoba, Spain
                [6 ] Division of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Berne, Berne, Switzerland
                [7 ] Swiss National Stud, Avenches, Switzerland
                [8 ] Swiss College of Agriculture, Zollikofen, Switzerland
                University of Oxford, United Kingdom
                Author notes
                * To whom correspondence should be addressed. E-mail: Tosso.Leeb@ 123456itz.unibe.ch
                Article
                07-PLGE-RA-0584R2 plge-03-11-08
                10.1371/journal.pgen.0030195
                2065884
                17997609
                ce0e068c-66dc-40b0-bb7b-e5144518bd85
                Copyright: © 2007 Haase et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 31 July 2007
                : 24 September 2007
                Page count
                Pages: 8
                Categories
                Research Article
                Dermatology
                Genetics and Genomics
                Horse
                Mammals
                Vertebrates
                Animals
                Eukaryotes
                Custom metadata
                Haase B, Brooks SA, Schlumbaum A, Azor PJ, Bailey E, et al. (2007) Allelic heterogeneity at the equine KIT locus in dominant white ( W) horses. PLoS Genet 3(11): e195. doi: 10.1371/journal.pgen.0030195

                Genetics
                Genetics

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