title: A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus).
abstract: The glaucomas are a group of diseases characterized by optic nerve damage that together represent a leading cause of blindness in the human population and in domestic animals. Here we report a mutation in LTBP2 that causes primary congenital glaucoma (PCG) in domestic cats. We identified a spontaneous form of PCG in cats and established a breeding colony segregating for PCG consistent with fully penetrant, autosomal recessive inheritance of the trait. Elevated intraocular pressure, globe enlargement and elongated ciliary processes were consistently observed in all affected cats by 8 weeks of age. Varying degrees of optic nerve damage resulted by 6 months of age. Although subtle lens zonular instability was a common feature in this cohort, pronounced ectopia lentis was identified in less than 10% of cats examined. Thus, glaucoma in this pedigree is attributed to histologically confirmed arrest in the early post-natal development of the aqueous humor outflow pathways in the anterior segment of the eyes of affected animals. Using a candidate gene approach, significant linkage was established on cat chromosome B3 (LOD 18.38, θ = 0.00) using tightly linked short tandem repeat (STR) loci to the candidate gene, LTBP2. A 4 base-pair insertion was identified in exon 8 of LTBP2 in affected individuals that generates a frame shift that completely alters the downstream open reading frame and eliminates functional domains. Thus, we describe the first spontaneous and highly penetrant non-rodent model of PCG identifying a valuable animal model for primary glaucoma that closely resembles the human disease, providing valuable insights into mechanisms underlying the disease and a valuable animal model for testing therapies.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Kuehn
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America.|Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania, United States of America.
authors.forename: Koren A
authors.initials: KA
authors.lastname: Lipsett
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Menotti-Raymond
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: S Scott
authors.initials: SS
authors.lastname: Whitmore
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America.|Basic Research Laboratory, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Victor A
authors.initials: VA
authors.lastname: David
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America.|Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russia.|Oceanographic Center, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.affiliation: Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania, United States of America.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Animal Science, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Jackie K
authors.initials: JK
authors.lastname: Jens
authors.affiliation: Department of Animal Science, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Elizabeth M
authors.identifier: 0000-0003-1482-2876
authors.initials: EM
authors.lastname: Snella
authors.affiliation: Department of Animal Science, Iowa State University, Ames, Iowa, United States of America.|Department of Veterinary Clinical Sciences, Iowa State University, Ames, Iowa, United States of America.
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Surgical Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|McPherson Eye Research Institute, Madison, Wisconsin, United States of America.
authors.forename: Gillian J
authors.initials: GJ
authors.lastname: McLellan
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000502:physiology; D002371:Cat Diseases / Q000151:congenital / Q000235:genetics*; D002415:Cats; D005260:Female; D008040:Genetic Linkage; D005901:Glaucoma / Q000151:congenital / Q000235:genetics / Q000662:veterinary*; D007429:Intraocular Pressure / Q000235:genetics; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012165:Retinal Ganglion Cells / Q000473:pathology
chemical_list: D053779:Latent TGF-beta Binding Proteins