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

Autoři: Maria Kaukonen aff001;  Ileana B. Quintero aff001;  Abdul Kadir Mukarram aff004;  Marjo K. Hytönen aff001;  Saila Holopainen aff001;  Kaisa Wickström aff006;  Kaisa Kyöstilä aff001;  Meharji Arumilli aff001;  Sari Jalomäki aff007;  Carsten O. Daub aff004;  Juha Kere aff003;  Hannes Lohi aff001
Působiště autorů: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland aff001;  Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland aff002;  Folkhälsan Research Center, Helsinki, Finland aff003;  Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden aff004;  Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland aff005;  Veterinary Clinic Kamu, Oulu, Finland aff006;  Veterinary Clinic Malmin Eläinklinikka Apex, Helsinki, Finland aff007;  Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden aff008;  Stem Cells and Metabolism Research Program STEMM, University of Helsinki, Helsinki, Finland aff009
Vyšlo v časopise: A putative silencer variant in a spontaneous canine model of retinitis pigmentosa. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008659
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008659


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.

Klíčová slova:

Dogs – Genetics of disease – Genome-wide association studies – Haplotypes – Human genetics – Pets and companion animals – Retinitis pigmentosa – Sequence motif analysis


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