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.

Cataracts in a population of Bengal cats in France

“…In the feline species, ocular disorders with a well‐established inheritance pattern include ocular lesions secondary to lysosomal storage disorders, primary congenital glaucoma, retinal dystrophies, and progressive retinal atrophy . Despite the recent and rapid expansion of the Bengal breed and the frequency of ocular abnormalities reported in some of the founder breeds (Burmese, Abyssinians, Siamese), to date, the only report of a hereditary ocular abnormality in the Bengal cat breed is a recent description of an early onset autosomal recessive retinal degeneration …”

Relationship between corneal sensitivity, corneal thickness, corneal diameter, and intraocular pressure in normal cats and cats with congenital glaucoma

“…Forty adult domestic cats ( Felis catus ) that were housed in a laboratory animal facility at the University of Wisconsin‐Madison for the purposes of other long‐term, noninvasive studies (electrophysiology and ocular imaging) were used opportunistically for this study, between other testing events. Nineteen cats (13 males and 6 females) with FCG that were homozygous for an LTBP2 gene mutation were evaluated in the glaucoma group, and 21 normal cats (11 males and 10 females) were included in the age‐matched control group. All subjects were domestic short‐hair cats and were sexually intact.…”

“…Glaucoma appears to be less prevalent in cats than in dogs, but this difference may reflect under‐diagnosis of feline glaucoma, due to insidious onset and relatively subtle clinical signs in cats that include mydriasis and globe enlargement . A form of inherited primary feline congenital glaucoma (FCG) was identified in Siamese cats, and a viable mixed‐breed colony established that provides a valuable model for the study of glaucoma pathophysiology in cats as well as humans . Corneal enlargement, often associated with more generalized globe enlargement, or buphthalmos, is a common secondary feature of chronic glaucoma in adult dogs and cats, and in both FCG and primary congenital glaucoma (PCG) in humans .…”

Structural and functional imaging of aqueous humour outflow: a review

“…In the future, aqueous angiography will be directed at comparing normal and glaucomatous eyes. This can be done with human subjects or glaucoma animal models (cat, dog or rodent) . The former is more clinically relevant, but careful attention will be required to exclude patients with low‐pressure glaucoma.…”

“…This can be done with human subjects or glaucoma animal models (cat, dog or rodent). 67 The former is more clinically relevant, but careful attention will be required to exclude patients with lowpressure glaucoma. Without drug holidays, maximum IOPs are not always known for all glaucoma patient.…”