Linkage mapping of the primary disease locus for collie eye anomaly Jennifer K. Lowe, a,b Anna V. Kukekova, c Ewen F. Kirkness, d Mariela C. Langlois, a Gustavo D. Aguirre, c Gregory M. Acland, c, * and Elaine A. Ostrander a a Division of Human Biology and Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-100, Seattle, WA 98109-1024, USA b Molecular and Cellular Biology Program, University of Washington, Box 357275, Seattle, WA 98195-7275, USA c Center for Canine Genetics and Reproduction, James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 47 Hungerford Road, Ithaca, NY 14853-6401, USA d The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850, USA Received 2 December 2002; accepted 27 February 2003 Abstract Collie eye anomaly (cea) is a hereditary ocular disorder affecting development of the choroid and sclera segregating in several breeds of dog, including rough, smooth, and Border collies and Australian shepherds. The disease is reminiscent of the choroidal hypoplasia phenotype observed in humans in conjunction with craniofacial or renal abnormalities. In dogs, however, the clinical phenotype can vary significantly; many dogs exhibit no obvious clinical consequences and retain apparently normal vision throughout life, while severely affected animals develop secondary retinal detachment, intraocular hemorrhage, and blindness. We report genetic studies establishing that the primary cea phenotype, choroidal hypoplasia, segregates as an autosomal recessive trait with nearly 100% penetrance. We further report linkage mapping of the primary cea locus to a 3.9-cM region of canine chromosome 37 (LOD = 22.17 at  = 0.076), in a region corresponding to human chromosome 2q35. These results suggest the presence of a developmental regulatory gene important in ocular embryogenesis, with potential implications for other disorders of ocular vascularization. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Dog; Collie; Canine; Linkage mapping; Eye; Choroid Collie eye anomaly (cea) 1 is an inherited canine ocular disorder characterized by regional hypoplasia of the cho- roid, the highly vascularized layer of the eye that supplies blood and nutrients to the retina, and resulting in an oph- thalmoscopically detectable window defect in the ocular fundus located temporal to the optic nerve. Defects of the sclera, characterized by colobomatous lesions, may also occur, presenting as pits within or engulfing the optic nerve head or in the adjacent fundus. Occasionally, tortuous reti- nal vessels and multiple retinal folds are also observed [37,39,40]. Mildly to moderately affected individuals ap- pear to retain normal visual function throughout life as determined by behavioral observation and clinical electro- retinography. However, severely affected dogs, particularly those with colobomas, can develop retinal detachments leading to blindness. In these, subretinal and preretinal neo- vascularization and intraocular hemorrhage can occur. The disease is reminiscent of the chorioretinal abnormalities observed in association with such disorders as Alagille or renal– coloboma syndromes (MIM Nos. 118450 and 120330, respectively). In canines, however, the cea pheno- type is limited to the eye. Cea is widespread in dogs, with a prevalence of 70 –97% for rough and smooth collies in the United States and Great Supplementary data associated with this article can be found at doi: 10.1016/S0888-7543(03)00078-8 and http://www.fhcrc.org/science/dog_ genome/dog.html.  Sequence data from this article have been deposited with the Gen- Bank Data Library under Accession Nos. AY197354 through AY197370. * Corresponding author. Fax: +1-607-256-5689. E-mail address: gma2@cornell.edu (G.M. Acland). 1 Abbreviations used: cea, collie eye anomaly; STS, sequence-tagged site; CFA, Canis familiaris autosome; RH, radiation hybrid; SNP, single nucleotide polymorphism. R Available online at www.sciencedirect.com Genomics 82 (2003) 86 –95 www.elsevier.com/locate/ygeno 0888-7543/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0888-7543(03)00078-8