title: Increased expression of MERTK is associated with a unique form of canine retinopathy.
abstract: Progressive retinal degenerations are among the most common causes of blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) resembles human retinitis pigmentosa (RP) and is typically characterized by a progressive loss of rod photoreceptors followed by a loss of cone function. The disease gradually progress from the loss of night and day vision to a complete blindness. We have recently described a unique form of retinopathy characterized by the multifocal gray/brown discoloration and thinning of the retina in the Swedish Vallhund (SV) breed. We aimed to identify the genetic cause by performing a genome wide association analysis in a cohort of 18 affected and 10 healthy control dogs using Illumina's canine 22k SNP array. We mapped the disease to canine chromosome 17 (p = 7.7×10(-5)) and found a 6.1 Mb shared homozygous region in the affected dogs. A combined analysis of the GWAS and replication data with additional 60 dogs confirmed the association (p = 4.3×10(-8), OR = 11.2 for homozygosity). A targeted resequencing of the entire associated region in four cases and four controls with opposite risk haplotypes identified several variants in the coding region of functional candidate genes, such as a known retinopathy gene, MERTK. However, none of the identified coding variants followed a compelling case- or breed-specific segregation pattern. The expression analyses of four candidate genes in the region, MERTK, NPHP1, ANAPC1 and KRCC1, revealed specific upregulation of MERTK in the retina of the affected dogs. Collectively, these results indicate that the retinopathy is associated with overexpression of MERTK, however further investigation is needed to discover the regulatory mutation for the better understanding of the disease pathogenesis. Our study establishes a novel gain-of-function model for the MERTK biology and provides a therapy model for retinopathy MERTK inhibitors. Meanwhile, a marker-based genetic counseling can be developed to revise breeding programs.
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Saija J
authors.initials: SJ
authors.lastname: Ahonen
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Meharji
authors.initials: M
authors.lastname: Arumilli
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Seppälä
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Osmo
authors.initials: O
authors.lastname: Hakosalo
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Kaukonen
authors.affiliation: 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.
authors.forename: András M
authors.initials: AM
authors.lastname: Komáromy
authors.affiliation: Department of Veterinary Biosciences and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
mesh_terms: D000818:Animals; D018450:Disease Progression; D004283:Dog Diseases / Q000201:enzymology / Q000235:genetics; D004285:Dogs; D015971:Gene Expression Regulation, Enzymologic; D055106:Genome-Wide Association Study; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D012164:Retinal Diseases / Q000201:enzymology / Q000235:genetics / Q000662:veterinary*
chemical_list: D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases