A putative silencer variant in a spontaneous canine model of retinitis pigmentosa

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Kaukonen , M , Quintero , I B , Mukarram , A K , Hytönen , M K , Holopainen , S , Wickström , K , Kyöstilä , K , Arumilli , M , Jalomäki , S , Daub , C O , Kere , J , Lohi , H & Consortium , T DA 2020 , ' A putative silencer variant in a spontaneous canine model of retinitis pigmentosa ' , PLoS Genetics , vol. 16 , no. 3 , 1008659 . https://doi.org/10.1371/journal.pgen.1008659

Title: A putative silencer variant in a spontaneous canine model of retinitis pigmentosa
Author: Kaukonen, Maria; Quintero, Ileana B.; Mukarram, Abdul Kadir; Hytönen, Marjo K.; Holopainen, Saila; Wickström, Kaisa; Kyöstilä, Kaisa; Arumilli, Meharji; Jalomäki, Sari; Daub, Carsten O.; Kere, Juha; Lohi, Hannes; Consortium, the DoGA
Contributor organization: Hannes Tapani Lohi / Principal Investigator
Veterinary Biosciences
Department of Medical and Clinical Genetics
Veterinary Genetics
Small Animal Hospital
Equine and Small Animal Medicine
STEMM - Stem Cells and Metabolism Research Program
Research Programs Unit
Helsinki One Health (HOH)
Date: 2020-03-09
Language: eng
Number of pages: 20
Belongs to series: PLoS Genetics
ISSN: 1553-7390
DOI: https://doi.org/10.1371/journal.pgen.1008659
URI: http://hdl.handle.net/10138/314668
Abstract: Author summary Retinitis pigmentosa (RP) is a blinding eye disease that affects nearly two million people worldwide. Several genes and variants have been associated with the disease, but still 30-80% of the patients lack genetic diagnosis. There is currently no standard treatment for RP, and much is expected from gene therapy. A similar disease, called progressive retinal atrophy (PRA), affects many dog breeds. We performed clinical, genetic and functional analyses to find the genetic cause for PRA in Miniature Schnauzers. We discovered two forms of PRA in the breed, named type 1 and 2, and show that they are genetically distinct as they map to different chromosomes, 15 and X, respectively. Further genetic, bioinformatic and functional analyses discovered a fully penetrant recessive variant in a putative silencer region for type 1 PRA. Silencer regions are important for gene regulation and we found that two of its predicted target genes, EDN2 and COL9A2, were overexpressed in the retina of the affected dog. Defects in both EDN2 and COL9A2 have been associated with retinal degeneration. This study provides new insights to retinal biology while the genetic test guides better breeding choices. Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30-80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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