1. Mapping and characterization of the gene/mutation causative of the white, deaf phenotype. It is well established that hearing and pigmentation of the skin and fur are linked, and that a small population of melanocytes within the inner ear is essential for hearing. Melanocytes populate the stria vascularis, the structure responsible for generating the endolymph in the cochlea. In the last decade, several syndromic deafness genes have been identified that produce both deafness and systemic pigment cell abnormalities. In cats, the allele W of the biallelic autosomal dominant White locus is dominant and epistatic over all color loci. We have mapped the gene for dominant white segregating in a white, deaf pedigree to the c-kit locus (theta = 0, lod = 6.3). We have additionally characterized the insertion of a retroposon into a c-kit genomic region, highly conserved across mammals, and previously identified as an enhancer element involved in tissue specific expression. kit locus encodes a transmembrane receptor of the cytokine stem cell factor (Kit ligand) and is critical in the proliferation, survival and migration of multiple stem cell types, including melanoblasts. 2. Characterization of a new domestic cat model of human primary and secondary glaucoma with mutation detection in our mapped locus, LTBP2, of feline pediatric glaucoma. Primary congenital glaucoma is the most frequent childhood glaucoma and an important cause of childhood blindness, affecting approximately 1 in 10,000 children born in the USA. We previously mapped a gene causative of primary congenital glaucoma segregating in a cat pedigree (maintained at Iowa State University), to LTBP2 (chromosome B3) (theta= 0, lod = 18.38). The causative mutation, a premature stop codon, has been characterized in LTBP2, thus identifying the first animal model for this human pathology. 3. Characterization of the locus causative of pattern formation in the domestic cat, identifies a new regulator of Edn3/Ednrb signalling. We have characterized the gene which underlies pattern formation in the domestic cat by upregulating paracrine expression of Endothelin 3 (EDN3) (Kaelin et al., submitted, Genetics of coat pattern in the domestic cat). The gene is conserved across mammals, but is of largely unknown function. In mice, EDN3 has been implicated previously in hyperpigmentation, with the demonstration that an EDN3 transgene and a hypermorphic allele of Gq (the second messenger through which EDN3 acts) elicit an increased ratio of eumelanin to pheomelanin synthesis. Activating mutations in another gene, GNAQ, in this same pathway have been found in a large proportion of uveal melanoma tumors. The endothelins are among the major paracrine factors involved in melanocyte biology. EDN3 signaling, via the G-coupled EDN receptor type B (EDNRB), is critical for the development of melanocytes, promoting the survival, proliferation, differentiation and migration of melanocyte precursors. We have thus identified a novel component that regulates EDN3/EDNRB signaling, a pathway recognized as critical in the progression and metastasis of melanoma.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Menotti-Raymond, M; David, V A; Pflueger, S et al. (2010) Widespread retinal degenerative disease mutation (rdAc) discovered among a large number of popular cat breeds. Vet J 186:32-8
Eizirik, Eduardo; David, Victor A; Buckley-Beason, Valerie et al. (2010) Defining and mapping mammalian coat pattern genes: multiple genomic regions implicated in domestic cat stripes and spots. Genetics 184:267-75
Menotti-Raymond, Marilyn; Deckman, Koren Holland; David, Victor et al. (2010) Mutation discovered in a feline model of human congenital retinal blinding disease. Invest Ophthalmol Vis Sci 51:2852-9
Driscoll, Carlos A; Clutton-Brock, Juliet; Kitchener, Andrew C et al. (2009) The Taming of the cat. Genetic and archaeological findings hint that wildcats became housecats earlier--and in a different place--than previously thought. Sci Am 300:68-75
Menotti-Raymond, Marilyn; David, Victor A; Schäffer, Alejandro A et al. (2009) An autosomal genetic linkage map of the domestic cat, Felis silvestris catus. Genomics 93:305-13
Menotti-Raymond, Marilyn; David, Victor A; Eizirik, Eduardo et al. (2009) Mapping of the domestic cat ""SILVER"" coat color locus identifies a unique genomic location for silver in mammals. J Hered 100 Suppl 1:S8-13
Schmidt-Küntzel, Anne; Nelson, George; David, Victor A et al. (2009) A domestic cat X chromosome linkage map and the sex-linked orange locus: mapping of orange, multiple origins and epistasis over nonagouti. Genetics 181:1415-25
Driscoll, Carlos A; Yamaguchi, Nobuyuki; Bar-Gal, Gila Kahila et al. (2009) Mitochondrial phylogeography illuminates the origin of the extinct caspian tiger and its relationship to the amur tiger. PLoS One 4:e4125
Menotti-Raymond, Marilyn; David, Victor A; Pflueger, Solveig M et al. (2008) Patterns of molecular genetic variation among cat breeds. Genomics 91:1-11