TY - JOUR
T1 - A putative silencer variant in a spontaneous canine model of retinitis pigmentosa
AU - DoGA Consortium
AU - Kaukonen, Maria
AU - Quintero, Ileana B.
AU - Mukarram, Abdul Kadir
AU - Hytönen, Marjo K.
AU - Holopainen, Saila
AU - Wickström, Kaisa
AU - Kyöstilä, Kaisa
AU - Arumilli, Meharji
AU - Jalomäki, Sari
AU - Daub, Carsten O.
AU - Kere, Juha
AU - Lohi, Hannes
AU - Aguirre, Gus
AU - André, Catherine
AU - Bannasch, Danika
AU - Becker, Doreen
AU - Davis, Brian
AU - Drögemüller, Cord
AU - Ekenstedt, Kari
AU - Faller, Kiterie
AU - Forman, Oliver
AU - Friedenberg, Steve
AU - Furrow, Eva
AU - Giger, Urs
AU - Hitte, Christophe
AU - Jagannathan, Vidhya
AU - Leeb, Tosso
AU - Mellersh, Cathryn
AU - Mickelson, Jim
AU - Murgiano, Leonardo
AU - Oberbauer, Anita
AU - Schmutz, Sheila
AU - Schoenebeck, Jeffrey
AU - Summers, Kim
AU - van Steenbeck, Frank
AU - Wade, Claire
AU - Araujo, César L.
AU - Salonen, Milla
AU - Sarviaho, Riika
AU - Niskanen, Julia
AU - Hundi, Sruthi
AU - Puurunen, Jenni
AU - Sulkama, Sini
AU - Karjalainen, Sini
AU - Sukura, Antti
AU - Syrjä, Pernilla
AU - Airas, Niina
AU - Pekkarinen, Henna
AU - Kareinen, Ilona
AU - Knuuttila, Anna
N1 - Publisher Copyright:
© 2020 Kaukonen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1008659
DO - 10.1371/journal.pgen.1008659
M3 - Article
C2 - 32150541
AN - SCOPUS:85082144531
SN - 1553-7390
VL - 16
JO - PLoS genetics
JF - PLoS genetics
IS - 3
M1 - e1008659
ER -