Mammalian Genome

, Volume 23, Issue 1–2, pp 212–223 | Cite as

Genome-wide association study in RPGRIP1−/− dogs identifies a modifier locus that determines the onset of retinal degeneration

  • Keiko Miyadera
  • Kumiko Kato
  • Mike Boursnell
  • Cathryn S. Mellersh
  • David R. Sargan
Article

Abstract

Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1−/− dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1−/− MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10−13) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ~11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1−/− alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD.

Supplementary material

335_2011_9384_MOESM1_ESM.pdf (171 kb)
Supplementary material 1 (PDF 170 kb)

References

  1. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95PubMedGoogle Scholar
  2. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG (2005) Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther 12:1072–1082PubMedCrossRefGoogle Scholar
  3. Aguirre GD, Acland GM (2006) Models, mutants and man: searching for unique phenotypes and genes in the dog model of inherited retinal degeneration. In: Ostrander EA, Giger U, Lindblad-Toh K (eds) The dog and its genome. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 291–325Google Scholar
  4. Altshuler D, Daly M (2007) Guilt beyond a reasonable doubt. Nat Genet 39:813–815PubMedCrossRefGoogle Scholar
  5. Annear MJ, Bartoe JT, Barker SE, Smith AJ, Curran PG, Bainbridge JW, Ali RR, Petersen-Jones SM (2011) Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Ther 18:53–61PubMedCrossRefGoogle Scholar
  6. Badano JL, Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3:779–789PubMedCrossRefGoogle Scholar
  7. Bainbridge JW, Mistry A, Schlichtenbrede FC, Smith A, Broderick C, De Alwis M, Georgiadis A, Taylor PM, Squires M, Sethi C, Charteris D, Thrasher AJ, Sargan D, Ali RR (2003) Stable rAAV-mediated transduction of rod and cone photoreceptors in the canine retina. Gene Ther 10:1336–1344PubMedCrossRefGoogle Scholar
  8. Barnett KC (1965) Retinal atrophy. Vet Rec 77:1543–1560PubMedGoogle Scholar
  9. Batten ML, Imanishi Y, Maeda T, Tu DC, Moise AR, Bronson D, Possin D, Van Gelder RN, Baehr W, Palczewski K (2004) Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver. J Biol Chem 279:10422–10432PubMedCrossRefGoogle Scholar
  10. Beltran WA (2009) The use of canine models of inherited retinal degeneration to test novel therapeutic approaches. Vet Ophthalmol 12:192–204PubMedCrossRefGoogle Scholar
  11. Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z, Qu G, Zhou S, Zeiss C, Arruda VR, Acland GM, Dell’Osso LF, High KA, Maguire AM, Bennett J (2008) Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther 16:458–465PubMedCrossRefGoogle Scholar
  12. Busse C, Barnett KC, Mellersh CS, Adams VJ (2011) Ophthalmic and cone derived electrodiagnostic findings in outbred miniature long-haired dachshunds homozygous for a RPGRIP1 mutation. Vet Ophthalmol 14:146–152PubMedCrossRefGoogle Scholar
  13. Cideciyan AV, Jacobson SG, Aleman TS, Gu D, Pearce-Kelling SE, Sumaroka A, Acland GM, Aguirre GD (2005) In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa. Proc Natl Acad Sci USA 102:5233–5238PubMedCrossRefGoogle Scholar
  14. Curtis R, Barnett KC (1993) Progressive retinal atrophy in miniature longhaired dachshund dogs. Br Vet J 149:71–85PubMedGoogle Scholar
  15. den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27:391–419CrossRefGoogle Scholar
  16. Fauser S, Munz M, Besch D (2003) Further support for digenic inheritance in Bardet-Biedl syndrome. J Med Genet 40:e104PubMedCrossRefGoogle Scholar
  17. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809PubMedCrossRefGoogle Scholar
  18. Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, Sawyer L, Hendry G, Dhillon B, Milam AH, Luthert PJ, Swaroop A, Hastie ND, Jacobson SG, Wright AF (2003) Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Hum Mol Genet 12:2657–2667PubMedCrossRefGoogle Scholar
  19. Hoefele J, Wolf MT, O’Toole JF, Otto EA, Schultheiss U, Deschenes G, Attanasio M, Utsch B, Antignac C, Hildebrandt F (2007) Evidence of oligogenic inheritance in nephronophthisis. J Am Soc Nephrol 18:2789–2795PubMedCrossRefGoogle Scholar
  20. Jacobson SG, Cideciyan AV, Wright E, Wright AF (2001) Phenotypic marker for early disease detection in dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci 42:1882–1890PubMedGoogle Scholar
  21. Kajiwara K, Berson EL, Dryja TP (1994) Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264:1604–1608PubMedCrossRefGoogle Scholar
  22. Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ 3rd, Comstock KE, Keller ET, Mesirov JP, von Euler H, Kampe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K (2007) Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39:1321–1328PubMedCrossRefGoogle Scholar
  23. Kelsell RE, Gregory-Evans K, Payne AM, Perrault I, Kaplan J, Yang RB, Garbers DL, Bird AC, Moore AT, Hunt DM (1998) Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 7:1179–1184PubMedCrossRefGoogle Scholar
  24. Kennan A, Aherne A, Humphries P (2005) Light in retinitis pigmentosa. Trends Genet 21:103–110PubMedCrossRefGoogle Scholar
  25. Khanna H, Davis EE, Murga-Zamalloa CA, Estrada-Cuzcano A, Lopez I, den Hollander AI, Zonneveld MN, Othman MI, Waseem N, Chakarova CF, Maubaret C, Diaz-Font A, Macdonald I, Muzny DM, Wheeler DA, Morgan M, Lewis LR, Logan CV, Tan PL, Beer MA, Inglehearn CF, Lewis RA, Jacobson SG, Bergmann C, Beales PL, Attie-Bitach T, Johnson CA, Otto EA, Bhattacharya SS, Hildebrandt F, Gibbs RA, Koenekoop RK, Swaroop A, Katsanis N (2009) A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet 41:739–745PubMedCrossRefGoogle Scholar
  26. Louie CM, Caridi G, Lopes VS, Brancati F, Kispert A, Lancaster MA, Schlossman AM, Otto EA, Leitges M, Grone HJ, Lopez I, Gudiseva HV, O’Toole JF, Vallespin E, Ayyagari R, Ayuso C, Cremers FP, den Hollander AI, Koenekoop RK, Dallapiccola B, Ghiggeri GM, Hildebrandt F, Valente EM, Williams DS, Gleeson JG (2010) AHI1 is required for photoreceptor outer development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet 42:175–180PubMedCrossRefGoogle Scholar
  27. Mellersh CS, Boursnell ME, Pettitt L, Ryder EJ, Holmes NG, Grafham D, Forman OP, Sampson J, Barnett KC, Blanton S, Binns MM, Vaudin M (2006) Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88:293–301PubMedCrossRefGoogle Scholar
  28. Milam AH, Curcio CA, Cideciyan AV, Saxena S, John SK, Kruth HS, Malek G, Heckenlively JR, Weleber RG, Jacobson SG (2000) Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration. Ophthalmology 107:2256–2266PubMedCrossRefGoogle Scholar
  29. Miyadera K, Kato K, Aguirre-Hernandez J, Tokuriki T, Morimoto K, Busse C, Barnett K, Holmes N, Ogawa H, Sasaki N, Mellersh CS, Sargan DR (2009) Phenotypic variation and genotype–phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis 15:2287–2305PubMedGoogle Scholar
  30. Miyadera K, Acland GM, Aguiree GD (2012) Genetic and phenotypic variation of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome. doi:10.1007/s00335-011-9361-3
  31. Payne AM, Morris AG, Downes SM, Johnson S, Bird AC, Moore AT, Bhattacharya SS, Hunt DM (2001) Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies. J Med Genet 38:611–614PubMedCrossRefGoogle Scholar
  32. Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frezal J, Dufier JL, Pittler S, Munnich A, Kaplan J (1996) Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat Genet 14:461–464PubMedCrossRefGoogle Scholar
  33. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCrossRefGoogle Scholar
  34. Quignon P, Herbin L, Cadieu E, Kirkness EF, Hedan B, Mosher DS, Galibert F, Andre C, Ostrander EA, Hitte C (2007) Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies. PLoS One 2:e1324PubMedCrossRefGoogle Scholar
  35. Saari JC, Bredberg DL (1989) Lecithin:retinol acyltransferase in retinal pigment epithelial microsomes. J Biol Chem 264:8636–8640PubMedGoogle Scholar
  36. Saari JC, Bredberg DL, Farrell DF (1993) Retinol esterification in bovine retinal pigment epithelium: reversibility of lecithin:retinol acyltransferase. Biochem J 291(Pt 3):697–700PubMedGoogle Scholar
  37. Saffin JM, Venoux M, Prigent C, Espeut J, Poulat F, Giorgi D, Abrieu A, Rouquier S (2005) ASAP, a human microtubule-associated protein required for bipolar spindle assembly and cytokinesis. Proc Natl Acad Sci USA 102:11302–11307PubMedCrossRefGoogle Scholar
  38. Samardzija M, Wenzel A, Naash M, Reme CE, Grimm C (2006) Rpe65 as a modifier gene for inherited retinal degeneration. Eur J Neurosci 23:1028–1034PubMedCrossRefGoogle Scholar
  39. Sanyal S, Hawkins RK (1986) Development and degeneration of retina in rds mutant mice: effects of light on the rate of degeneration in albino and pigmented homozygous and heterozygous mutant and normal mice. Vision Res 26:1177–1185PubMedCrossRefGoogle Scholar
  40. Taylor HR, Munoz B, West S, Bressler NM, Bressler SB, Rosenthal FS (1990) Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc 88:163–173 discussion 173–168PubMedGoogle Scholar
  41. The Kennel Club/British Small Animal Veterinary Association Purebred Dog Health Survey (2004) http://www.thekennelclub.org.uk/item/549. Accessed 29 Sep 2011
  42. Thompson DA, Li Y, McHenry CL, Carlson TJ, Ding X, Sieving PA, Apfelstedt-Sylla E, Gal A (2001) Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Nat Genet 28:123–124PubMedCrossRefGoogle Scholar
  43. Turney C, Chong NH, Alexander RA, Hogg CR, Fleming L, Flack D, Barnett KC, Bird AC, Holder GE, Luthert PJ (2007) Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund. Invest Ophthalmol Vis Sci 48:4240–4249PubMedCrossRefGoogle Scholar
  44. Visel A, Zhu Y, May D, Afzal V, Gong E, Attanasio C, Blow MJ, Cohen JC, Rubin EM, Pennacchio LA (2010) Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464:409–412PubMedCrossRefGoogle Scholar
  45. Wang M, Lam TT, Tso MO, Naash MI (1997) Expression of a mutant opsin gene increases the susceptibility of the retina to light damage. Vis Neurosci 14:55–62PubMedCrossRefGoogle Scholar
  46. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284PubMedCrossRefGoogle Scholar
  47. Zhang H, Fan J, Li S, Karan S, Rohrer B, Palczewski K, Frederick JM, Crouch RK, Baehr W (2008) Trafficking of membrane-associated proteins to cone photoreceptor outer segments requires the chromophore 11-cis-retinal. J Neurosci 28:4008–4014PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Keiko Miyadera
    • 1
    • 1
    • 4
  • Kumiko Kato
    • 2
  • Mike Boursnell
    • 3
  • Cathryn S. Mellersh
    • 3
  • David R. Sargan
    • 1
  1. 1.Department of Veterinary MedicineUniversity of CambridgeCambridgeUK
  2. 2.Department of Veterinary Medical Science, Graduate School of Agricultural and Life SciencesUniversity of TokyoBunkyo-kuJapan
  3. 3.Centre for Preventive MedicineAnimal Health TrustKentford, NewmarketUK
  4. 4.Section of Ophthalmology, Department of Clinical Studies, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations