Natural models for retinitis pigmentosa: progressive retinal atrophy in dog breeds

Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders eventually leading to blindness with different ages of onset, progression and severity. Human RP, first characterized by the progressive degeneration of rod photoreceptor cells, shows high genetic heterogeneity with more than 90 genes identified. However, about one-third of patients have no known genetic causes. Interestingly, dogs are also severely affected by similar diseases, called progressive retinal atrophy (PRA). Indeed, RP and PRA have comparable clinical signs, physiopathology and outcomes, similar diagnosis methods and most often, orthologous genes are involved. The many different dog PRAs often segregate in specific breeds. Indeed, undesired alleles have been selected and amplified through drastic selection and excessive use of inbreeding. Out of the 400 breeds, nearly 100 have an inherited form of PRA, which are natural animal models that can be used to investigate the genetics, disease progression and therapies in dogs for the benefit of both dogs and humans. Recent knowledge on the canine genome and access to new genotyping and sequencing technologies now efficiently allows the identification of mutations involved in canine genetic diseases. To date, PRA genes identified in dog breeds correspond to the same genes in humans and represent relevant RP models, and new genes found in dogs represent good candidate for still unknown human RP. We present here a review of the main advantages of the dog models for human RP with the genes already identified and an X-linked PRA in the Border collie as a model for orphan X-linked RPs in human.

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Acknowledgements

Authors dedicate this publication to Christian Hamel who tragically passed away during the writing of this paper. With great humility and sincerity, we dedicate this work to him. The authors are grateful to French referring veterinarians and to all dog owners and breeders who donated samples, pedigree data and follow-up of their dogs, especially the AFBC (Association Française du Border Collie), Mr. Cornuet, Mr. Fournier, Mr. Brimboeuf and Mrs Chartier, for transmitting the official eye clinical examination results as well as the ACT 43 (Association des Chiens de Troupeau de la Haute Loire) for participating to the funding of the whole genome sequencing of 3 dogs. We do thank breeders who welcome our research team in their kennels several years for sampling dogs, notably Mrs Malafayde, Mr. and Mrs Lalande, Mr and Mrs Laurent, Mr Garnier and Mrs Ladousse. We thank A.S. Lequarré and M.L Ramos-Pamplona, as coordinators for the European FP7 LUPA project, A. Boland and D. Zelenika for the genotyping performed at CNG, Evry, France. We do thank the members of DBVDC, dog whole genome sequencing consortium: Gus Aguirre, Catherine André, Danika Bannasch, Doreen Becker, Brian Davis, Cord Drögemüller, Kari Ekenstedt, Kiterie Faller, Oliver Forman, Steve Friedenberg, Eva Furrow, Urs Giger, Christophe Hitte, Marjo Hytönen, Tosso Leeb, Hannes Lohi, Cathryn Mellersh, Jim Mickelson, Leonardo Murgiano, Anita Oberbauer, Sheila Schmutz, Jeffrey Schoenebeck, Kim Summers, Frank van Steenbeek, Claire Wade. Blood and tissue samples from dogs were collected by a network of veterinarians through the Cani-DNA CRB (http://dog-genetics.genouest.org), which is part of the CRB-Anim infrastructure, ANR-11-INBS-0003. We thank Dr. Amandine Olivier for clinical data, Dr. Estèle Lafont for past molecular genetics experiments and the picture of the blind Border collie of Fig. 3, as well as Solenne Correard and Mélanie Rault for helpful discussions and advices. We also thank Antagene, Animal genetics laboratory, especially Anne Thomas and Guillaume Queney, for their involvement in the Border collie PRA project.

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Bunel, M., Chaudieu, G., Hamel, C. et al. Natural models for retinitis pigmentosa: progressive retinal atrophy in dog breeds. Hum Genet 138, 441–453 (2019). https://doi.org/10.1007/s00439-019-01999-6

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