A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus)

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

Cats: A Gold Mine for Ophthalmology

Over 200 hereditary diseases have been identified and reported in the cat, several of which affect the eye, with homology to human hereditary disease. Compared with traditional murine models, the cat demonstrates more features in common with humans, including many anatomic and physiologic similarities, longer life span, increased size, and a genetically more heterogeneous background. The development of genomic resources in the cat has facilitated mapping and further characterization of feline models. During recent years, the wealth of knowledge in feline ophthalmology and neurophysiology has been extended to include new diseases of significant interest for comparative ophthalmology. This makes the cat an extremely valuable animal species to utilize for further research into disease processes affecting both cats and humans. This is especially true in the advancement and study of new treatment regimens and for extended therapeutic trials. Groups of feline eye diseases reviewed in the following are lysosomal storage disorders, congenital glaucoma, and neuroretinal degenerations. Each has important implications for human ophthalmic research

Correction: A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus).

[This corrects the article DOI: 10.1371/journal.pone.0154412.]

Feline congenital glaucoma pedigree.

<p>Additional pairings between affected and affected animals consistently produced all affected offspring but are not depicted in this informative pedigree. Females are depicted by circles and males by squares, diamonds indicate gender not recorded. Black shapes indicate that PCG phenotype confirmed by clinical examination conducted by a board certified veterinary ophthalmologist. Unfilled shapes indicate normal phenotype confirmed on clinical examination. Light gray shading with strike-through indicates that phenotype was not confirmed. Asterisks indicate those animals from which DNA samples were obtained and used in linkage analysis and/ or gene sequencing.</p

Preservation of Normal Outer Retinal Structure in Feline Primary Congenital Glaucoma.

<p>Representative fluorescence photomicrographs of DAPI stained 18 month old glaucomatous [A] and normal 6 month old [B] feline retinas. No significant difference in morphology of outer retinal layers is identified. (GCL = ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; OPL = outer plexiform layer; ONL = outer nuclear layer; RPE = retinal pigment epithelium).</p

Sequences of Exon 8 of <i>LTBP2</i> in Normal Cat and in Primary Congenital Glaucoma.

<p>Sanger sequencing results of exon 8 of <i>LTBP2</i> in a normal (top) and a PCG-affected (bottom) individual. Analysis reveals a 4bp insertion in all affected individuals (boxed). Coordinates are for chromosome B3 from the felCat5 genome build.</p

Optic Neuropathy in Feline Primary Congenital Glaucoma.

<p>Mean axon count in PCG cats (66 eyes of 38 cats aged 4 months to 8 years) is significantly lower (44,438 ± 2,272 [SEM]) than in normal cats (mean = 70,510 ± 1,535 in 33 eyes of 20 normal cats; p<0.0001, unpaired t-test). Lines represent mean and error bars represent SD.</p

Clinical Appearance of Feline Primary Congenital Glaucoma.

<p>Iris hypoplasia and ectopia lentis in feline PCG. The outline of the posteriorly subluxated lens can be readily appreciated through thin, translucent iris tissue in this affected Siamese cat.</p

Coverage across Feline LTBP2 exons by RNA-Seq.

<p>RNA-Seq read coverage across the <i>LTBP2</i> exons within the cat genome. Coordinates are shown in genomic orientation. The numeric range in the top left indicates the minimum and maximum number of reads (FPKM-Fragments Per Kilobase of exon per Million) per base for the sample.</p

Optic Nerve Head Cupping in Feline Primary Congenital Glaucoma.

<p>Fundus photographs illustrate the cupped and degenerate optic nerve head of [A] a cat with advanced primary congenital glaucoma and compared with a normal age-matched cat [B]. An optic nerve cube scan obtained by spectral domain optical coherence tomography (OCT;Cirrus, Carl Zeiss Meditec Inc., Dublin, CA) acquired in this affected cat confirms dramatic posterior displacement of the lamina cribrosa (LC, arrowed)[C] compared to the normal control[D]. (Modified, with permission, from McLellan GJ, Rasmussen CA. Optical coherence tomography for the evaluation of retinal and optic nerve morphology in animal subjects: practical considerations. Veterinary Ophthalmology. Sep 2012;15 Suppl 2:13–28.).</p