Current Science

Open Access Open Access  Restricted Access Subscription Access

Identification of Genetic Variants in PDC, RHO, PDE6A and PDE6B in Dogs with Progressive Retinal Atrophy


Affiliations
1 Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
2 Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
 

The progressive retinal atrophy (PRA) is an inherited eye disease and characterized by progressive retinal degeneration which leads to impaired vision in dogs. Using targeted next generation sequencing of nine PRA cases and six controls, we have identified SNPs in PDC, PDE6A and PDE6B, which were not previously associated with PRA. The gene in which the highest mutations found was PDE6A (113 and 104 SNPs), followed by PDE6B, PDC and RHO in all dog breeds and Spitz-only respectively. Five SNPs identified in PDC gene of Spitz-only breed showed significant association with PRA. However, no pathogenetically relevant mutations were found in RHO gene for PRA. The SNP in PDE6B chr3: 91763017 (G/A) in Spitz-only breed, and PDE6A chr4: 5912574 (T/C) and PDC chr7: 19511750 (T/A) were associated with PRA in the breeds of dog studied. Our results show that PRA is genetically heterogeneous and is caused by multiple, distinct mutations.

Keywords

Genome-Wide Association, Next Generation Sequencing, Progressive Retinal Atrophy, Single Nucleotide Polymorphisms.
User
Notifications
Font Size

  • Petersen-Jones, S., Advances in the molecular understanding of canine retinal diseases. J. Small Anim. Pract., 2005, 46(8), 371–380.

  • Downs, L. M., Wallin-Hakansson, B. and Boursnell, M., A frameshift mutation in golden retriever dogs with progressive reti-nal atrophy endorses SLC4A3 as a candidate gene for human reti-nal degenerations. PLoS ONE, 2011, 6(6), e21452.

  • Parry, H. B., Degenerations of the dog retina. II. Generalized pro-gressive atrophy of hereditary origin. Br. J. Ophthalmol., 1953, 37(8), 487–502.

  • Petersen-Jones, S. M., Animal models of human retinal dystro-phies. Eye (London), 1998, 12(Pt 3b), 566–570.

  • Vilboux., T., Chaudieu, G. and Jeannin, P., Progressive retinal atro-phy in the Border Collie: a new XLPRA. BMC Vet. Res., 2008, 4, 10.

  • Zangerl, B., Goldstein, O. and Philp, A. R., Identical mutation in a novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa in humans. Genomics, 2006, 88(5), 551–563.

  • Miyadera, K., Acland, G. M. and Aguirre, G. D., Genetic and phe-notypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm. Genome, 2012, 23(1–2), 40–61.

  • Ahonen, S. J., Arumilli, M. and Lohi, H. A., CNGB1 frameshift mutation in papillon and phalene dogs with progressive retinal at-rophy. PLoS ONE, 2013, 8(8), e72122.

  • Grondahl, J., Estimation of prognosis and prevalence of retinitis pigmentosa and Usher syndrome in Norway. Clin. Genet., 1987, 31(4), 255–264.

  • Haim, M., Holm, N. V. and Rosenberg, T., Prevalence of retinitis pigmentosa and allied disorders in Denmark. I. Main results. Acta Ophthalmol., 1992, 70(2), 178–186.

  • Pagon, R. A., Retinitis pigmentosa. Surv. Ophthalmol., 1988, 33(3), 137–177.

  • Patterson, D. F., Pexieder, T., Schnarr, W. R., Navratil, T. and Alaili, R. A., Single major-gene defect underlying cardiac cono-truncal malformations interferes with myocardial growth during embryonic development: studies in the CTD line of keeshond dogs. Am. J. Hum. Genet., 1993, 52(2), 388–397.

  • Beggs, A. H., Bohm, J. and Snead, E., MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc. Natl. Acad. Sci. USA, 2010, 107(33), 14697–14702.

  • Sidjanin, D. J., Lowe, J. K. and McElwee, J. L., Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum. Mol. Genet. 2002, 11(16), 1823–1833.

  • Mellersh, C. S., Boursnell, M. E. and Pettitt, L., Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics, 2006, 88(3), 293–301.

  • McC. Howell, J., Fletcher, S., Kakulas, B. A., O’Hara, M., Lochmuller, H. and Karpati, G., Use of the dog model for Du-chenne muscular dystrophy in gene therapy trials. Neuromusc. Disord., 1997, 7(5), 325–328.

  • Acland, G. M., Aguirre, G. D. and Ray, J., Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet., 2001, 28(1), 92–95.

  • Ponder, K. P., Melniczek, J. R. and Xu, L., Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs. Proc. Natl. Acad. Sci. USA, 2002, 99(20), 13102–13107.

  • Bainbridge, J. W., Smith, A. J. and Barker, S. S., Effect of gene therapy on visual function in Leber’s congenital amaurosis. New Engl. J. Med., 2008, 358(21), 2231–2239.

  • Narfstrom, K., Jeong, M., Hyman, J., Madsen, R. W. and Berg-strom, T. F., Assessment of hereditary retinal degeneration in the English springer spaniel dog and disease relationship to an RPGRIP1 mutation. Stem Cells Int., 2012, 2012, 685901.

  • Suber, M. L., Pittler, S. J. and Qin, N., Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc. Natl. Acad. Sci., USA, 1993, 90(9), 3968–3972.

  • Dekomien, G., Runte, M., Godde, R. and Epplen, J. T., General-ized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene. Cytogenet. Genome Res., 2000, 90(3–4), 261–267.

  • Petersen-Jones, S. M., Entz, D. D. and Sargan, D. R., cGMP phos-phodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest. Ophth. Vis. Sci., 1999, 40(8), 1637–1644.

  • Zhang, Q., Acland, G. M., Parshall, C. J., Haskell, J., Ray, K. and Aguirre, G. D., Characterization of canine photoreceptor phosducin cDNA and identification of a sequence variant in dogs with photoreceptor dysplasia. Gene, 1998, 215(2), 231–239.

  • Kijas, J. W., Cideciyan, A. V. and Aleman, T. S., Naturally occur-ring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc. Natl. Acad. Sci. USA, 2002, 99(9), 6328–6333.

  • Kijas, J. W., Miller, B. J., Pearce-Kelling, S. E., Aguirre, G. D. and Acland, G. M., Canine models of ocular disease: outcross breedings define a dominant disorder present in the English mas-tiff and bull mastiff dog breeds. J. Hered., 2003, 94(1), 27–30.

  • McKenna, A., Hanna, M. and Banks, E., The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res., 2010, 20(9), 1297–1303.

  • Abe, T., Kikuchi, T. and Shinohara, T., The sequence of the human phosducin gene (PDC) and its 5-flanking region. Ge-nomics, 1994, 19(2), 369–372.

  • Lee, R. H., Fowler, A., McGinnis, J. F., Lolley, R. N. and Craft, C. M., Amino acid and cDNA sequence of bovine phosducin, a soluble phosphoprotein from photoreceptor cells. J. Biol. Chem., 1990, 265(26), 15867–15873.

  • Lee, R. H., Lieberman, B. S. and Lolley, R. N., Retinal accumula-tion of the phosducin/T beta gamma and transducin complexes in developing normal mice and in mice and dogs with inherited retinal degeneration. Exp. Eye Res., 1990, 51(3), 325–333.

  • Lin, C. T., Petersen-Jones, S. M. and Sargan, D. R., Isolation and investigation of canine phosducin as a candidate for canine gener-alized progressive retinal atrophies. Exp. Eye Res., 1998, 67(4), 473–480.

  • Palczewski, K., Kumasaka, T. and Hori, T., Crystal structure of rhodopsin: A G protein-coupled receptor. Science, 2000, 289(5480), 739–745.

  • Rattner, A., Sun, H. and Nathans, J., Molecular genetics of human retinal disease. Annu. Rev. Genet., 1999, 33, 89–131.

  • Yuan, L., Kawada, M., Havlioglu, N., Tang, H. and Wu, J. Y., Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. J. Neurosci., 2005, 25(3), 748–757.

  • Danciger, M., Blaney, J. and Gao, Y. Q., Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa. Genomics, 1995, 30(1), 1–7.

  • Huang, S. H., Pittler, S. J., Huang, X., Oliveira, L., Berson, E. L. and Dryja, T. P., Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nat. Genet., 1995, 11(4), 468–471.

  • McLaughlin, M. E., Ehrhart, T. L., Berson, E. L. and Dryja, T. P., Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retini-tis pigmentosa. Natl. Acad. Sci. USA, 1995, 92(8), 3249–3253.

  • Bowes, C., Li, T., Danciger, M., Baxter, L. C., Applebury, M. L. and Farber, D. B., Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature, 1990, 347(6294), 677–680.

  • Pittler, S. J. and Baehr, W., Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc. Natl. Acad. Sci. USA, 1991, 88(19), 8322–8326.

  • Clements, P. J., Gregory, C. Y., Peterson-Jones, S. M., Sargan, D. R. and Bhattacharya, S. S., Confirmation of the rod cGMP phos-phodiesterase beta subunit (PDE beta) nonsense mutation in affected rcd-1 Irish setters in the UK and development of a diag-nostic test. Curr. Eye Res., 1993, 12(9), 861–866.

  • Ray, K., Baldwin, V. J., Acland, G. M., Blanton, S. H. and Aguir-re, G. D., Cosegregation of codon 807 mutation of the canine rod cGMP phosphodiesterase beta gene and rcd1. Invest. Ophth. Vis. Sci., 1994, 35(13), 4291–4299.


Abstract Views: 210

PDF Views: 77




  • Identification of Genetic Variants in PDC, RHO, PDE6A and PDE6B in Dogs with Progressive Retinal Atrophy

Abstract Views: 210  |  PDF Views: 77

Authors

Dipal Y. Pandya
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Divyesh N. Kelawala
Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Namrata V. Patel
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Tejas M. Shah
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Anand B. Patel
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Nidhi R. Parmar
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Bhaskar Reddy
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Deepak B. Patil
Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India
Chaitanya G. Joshi
Department of Animal Biotechnology, College of Veterinary Science and Animal Husbandry, Anand Agricultural University, Anand 388 001, India

Abstract


The progressive retinal atrophy (PRA) is an inherited eye disease and characterized by progressive retinal degeneration which leads to impaired vision in dogs. Using targeted next generation sequencing of nine PRA cases and six controls, we have identified SNPs in PDC, PDE6A and PDE6B, which were not previously associated with PRA. The gene in which the highest mutations found was PDE6A (113 and 104 SNPs), followed by PDE6B, PDC and RHO in all dog breeds and Spitz-only respectively. Five SNPs identified in PDC gene of Spitz-only breed showed significant association with PRA. However, no pathogenetically relevant mutations were found in RHO gene for PRA. The SNP in PDE6B chr3: 91763017 (G/A) in Spitz-only breed, and PDE6A chr4: 5912574 (T/C) and PDC chr7: 19511750 (T/A) were associated with PRA in the breeds of dog studied. Our results show that PRA is genetically heterogeneous and is caused by multiple, distinct mutations.

Keywords


Genome-Wide Association, Next Generation Sequencing, Progressive Retinal Atrophy, Single Nucleotide Polymorphisms.

References





DOI: https://doi.org/10.18520/cs%2Fv111%2Fi10%2F1640-1648