A novel missense mutation in ADAMTS10 in Norwegian Elkhound primary glaucoma.
Primary glaucoma is one of the most common causes of irreversible blindness both in humans and in dogs. Glaucoma is an optic neuropathy affecting the retinal ganglion cells and optic nerve, and elevated intraocular pressure is commonly associated with the disease. Glaucoma is broadly classified into primary open angle (POAG), primary closed angle (PCAG) and primary congenital glaucoma (PCG). Human glaucomas are genetically heterogeneous and multiple loci have been identified. Glaucoma affects several dog breeds but only three loci and one gene have been implicated so far. We have investigated the genetics of primary glaucoma in the Norwegian Elkhound (NE). We established a small pedigree around the affected NEs collected from Finland, US and UK and performed a genome-wide association study with 9 cases and 8 controls to map the glaucoma gene to 750 kb region on canine chromosome 20 (praw = 4.93×10-6, pgenome = 0.025). The associated region contains a previously identified glaucoma gene, ADAMTS10, which was subjected to mutation screening in the coding regions. A fully segregating missense mutation (p.A387T) in exon 9 was found in 14 cases and 572 unaffected NEs (pFisher = 3.5×10-27) with a high carrier frequency (25.3%). The mutation interrupts a highly conserved residue in the metalloprotease domain of ADAMTS10, likely affecting its functional capacity. Our study identifies the genetic cause of primary glaucoma in NEs and enables the development of a genetic test for breeding purposes. This study establishes also a new spontaneous canine model for glaucoma research to study the ADAMTS10 biology in optical neuropathy.
Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
Saija J
SJ
Ahonen
Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
Maria
M
Kaukonen
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America.
Forrest D
FD
Nussdorfer
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America.
Christine D
CD
Harman
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America; Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
András M
AM
Komáromy
Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
Hannes
H
Lohi
D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000818:Animals; D004252:DNA Mutational Analysis; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D005901:Glaucoma / Q000235:genetics / Q000662:veterinary*; D020125:Mutation, Missense; D010375:Pedigree
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C494614:ADAMTS10 protein, human