Mapping of the Disease Locus and Identification of ADAMTS10 As a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma

Abstract

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…1 The microfibril hypothesis is based on genetic and biological evidence and is consistent with many key features of glaucoma that have been studied extensively. Genetic support for the microfibril hypothesis includes involvement of the microfibril-associated genes, LOXL1, 2 LTBP2, 3,4 and ADAMTS10 1 in glaucoma and the high prevalence of primary open-angle glaucoma in patients with Marfan syndrome, 5 which is caused by mutations in FBN1, the gene that encodes fibrillin-1, the main component of microfibrils.…”

“…25 A mutation in ADAMTS10 has been reported as likely causative for glaucoma in a canine model of hereditary primary open-angle glaucoma. 1,71 ADAMTS10 is a secreted matrix metalloproteinase that can cleave fibrillin-1. 72,73 Although its exact function is not known, a role for ADAMTS10 in microfibril structure and function was first suggested by the finding that Weill-Marchesani syndrome can be caused either by recessive ADAMTS10 mutations 74 or dominant mutations in FBN1.…”

Biomechanical Properties and Correlation With Collagen Solubility Profile in the Posterior Sclera of Canine Eyes With anADAMTS10Mutation

“…16 This nonsyndromic form of canine POAG is inherited as an autosomal recessive trait 17 and has been linked to a variant (G661R missense mutation) of the ADAMTS10 gene. 6 In humans, mutations in ADAMTS10 cause Weill-Marchesani syndrome, a connective tissue disorder that usually presents in childhood with short stature and/or ocular problems, including glaucoma. 18 The ADAMTS10 protein is a member of the ADAMTS family of secreted metalloproteinases that contribute to the formation and turnover of the extracellular matrix (ECM).…”

Genetics of eye disorders in the dog.

“…Retinal disorders can be categorized in various ways and the way in which they have been Cone-rod dystrophy CRD3 ADAM9 Glen of Imaal terrier [53,54] Primary open angle glaucoma POAG ADAMTS10 Beagle [147] Primary lens luxation PLL ADAMTS17 Multiple, mainly terrier breeds [129,132] Rod cone degeneration RCD4 C2orf71 Gordon Setter, Irish Setter, Tibetan Terrier [30] Generalised progressive retinal atrophy gPRA CCDC66 Schappendoes [28] Progressive retinal atrophy PRA CNGB1 Papillon [15,17] Cone degeneration CD CNGB3 Alaskan malamute [68] Cone degeneration CD CNGB3 German shorthaired pointer [69] Dwarfism with retinal dysplasia (oculoskeletal dysplasia) DRD2 (OSD2) COL9A2 Samoyed [90] Dwarfism with retinal dysplasia (oculoskeletal dysplasia) DRD1 (OSD1) COL9A3 Labrador retriever [90] Hereditary cataract HC, EHC HSF4 Staffordshire bull terrier, Boston terrier, French bulldog [103] Hereditary cataract HC HSF4 Australian Shepherd [107] Collie eye anomaly CEA NHEJ1 Collies [91] Cone-rod dystrophy NPHP4 Standard wirehaired dachshund [49] Photoreceptor dysplasia PD PDC Miniature schnauzer [13] Rod cone dysplasia RCD1 PDE6B Irish setter [2] Rod cone dysplasia RCD1 PDE6B Sloughi [3] Rod cone dysplasia RCD3 PDE6A Cardigan Welsh corgi [4] Progressive rod-cone degeneration PRCD PRCD Multiple breeds [23] Rod cone dysplasia RCD2 RD3 Collie [7] Autosomal dominant progressive retinal atrophy ADPRA RHO English mastiff [24] Congenital stationary night blindness CSNB RPE65 Briard [58,59] X-linked progressive retinal atrophy XLPRA2 RPGR Mixed breed dogs [18] X-linked progressive retinal atrophy XLPRA1 RPGR Siberian Husky, Samoyed [18] Cone-rod dystrophy CORD1 (CRD4) RPGRIP Dachshunds [38] Early retinal degeneration ERD STK38L Norwegian elkhound [11] Canine multifocal retinopathy CMR1…”

“…Autosomal recessive, primary open-angle glaucoma (POAG) has been very well characterized in the Beagle [142][143][144][145][146] and a Gly661Arg variant in ADAMTS10 has been associated with the condition in Beagles that developed elevated intraocular pressure from 8 to 16 months of age, due to increased resistance to outflow of aqueous humour despite normal appearing open iridocorneal angles [147].…”