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:
https://doi.org/10.1371/journal.pgen.1008659
Souhrn
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
Zdroje
1. Narayan DS, Wood JP, Chidlow G, Casson RJ. A review of the mechanisms of cone degeneration in retinitis pigmentosa. Acta Ophthalmol 2016;94(8):748–754. doi: 10.1111/aos.13141 27350263
2. Daiger S, Rossiter B, Greenberg J, Christoffels A, Hide W. Data services and software for identifying genes and mutations causing retinal degeneration. Invest Ophthalmol Vis Sci 1998;39:S295.
3. Daiger S, Sullivan L, Bowne S. Genes and mutations causing retinitis pigmentosa. Clin Genet 2013;84(2):132–141. doi: 10.1111/cge.12203 23701314
4. Bassuk AG, Zheng A, Li Y, Tsang SH, Mahajan VB. Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells. Sci Rep 2016 Jan 27;6:19969. doi: 10.1038/srep19969 26814166
5. Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 2005;438(7069):803–819. doi: 10.1038/nature04338 16341006
6. Lequarré A, Andersson L, André C, Fredholm M, Hitte C, Leeb T, et al. LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs. The Veterinary Journal 2011;189(2):155–159. doi: 10.1016/j.tvjl.2011.06.013 21752675
7. Groeneveld LF, Gregusson S, Guldbrandtsen B, Hiemstra SJ, Hveem K, Kantanen J, et al. Domesticated animal biobanking: land of opportunity. PLoS biology 2016;14(7):e1002523. doi: 10.1371/journal.pbio.1002523 27467395
8. Vaquer G, Dannerstedt FR, Mavris M, Bignami F, Llinares-Garcia J, Westermark K, et al. Animal models for metabolic, neuromuscular and ophthalmological rare diseases. Nature Reviews Drug Discovery 2013;12(4):287–305. doi: 10.1038/nrd3831 23493083
9. Slijkerman RW, Song F, Astuti GD, Huynen MA, van Wijk E, Stieger K, et al. The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies. Prog Retin Eye Res 2015;48:137–159. doi: 10.1016/j.preteyeres.2015.04.004 25936606
10. Parry HB. Degenerations of the dog retina. II. Generalized progressive atrophy of hereditary origin. Br J Ophthalmol 1953 Aug;37(8):487–502. doi: 10.1136/bjo.37.8.487 13081944
11. Zangerl B, Goldstein O, Philp AR, Lindauer SJ, Pearce-Kelling SE, Mullins RF, et al. 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. doi: 10.1016/j.ygeno.2006.07.007 16938425
12. Petersen-Jones SM, Komáromy AM. Dog models for blinding inherited retinal dystrophies. Human Gene Therapy Clinical Development 2014;26(1):15–26.
13. Miyadera K, Acland GM, Aguirre GD. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within-and across-breed studies. Mammalian Genome 2012;23(1–2):40–61. doi: 10.1007/s00335-011-9361-3 22065099
14. Kijas JW, Cideciyan AV, Aleman TS, Pianta MJ, Pearce-Kelling SE, Miller BJ, et al. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 2002 Apr 30;99(9):6328–6333. doi: 10.1073/pnas.082714499 11972042
15. Acland GM, Blanton SH, Hershfield B, Aguirre GD. XLPRA: A canine retinal degeneration inherited as an X‐linked trait. American Journal of Medical Genetics Part A 1994;52(1):27–33.
16. Zhang Q, Acland GM, Wu WX, Johnson JL, Pearce-Kelling S, Tulloch B, et al. Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 2002;11(9):993–1003. doi: 10.1093/hmg/11.9.993 11978759
17. Vilboux T, Chaudieu G, Jeannin P, Delattre D, Hedan B, Bourgain C, et al. Progressive retinal atrophy in the Border Collie: A new XLPRA. BMC veterinary research 2008;4(1):10.
18. Kropatsch R, Akkad DA, Frank M, Rosenhagen C, Altmüller J, Nürnberg P, et al. A large deletion in RPGR causes XLPRA in Weimaraner dogs. Canine genetics and epidemiology 2016;3(1):7.
19. Progressive retinal atrophy in the miniature schnauzer. Proc. Am. Coll. Vet. Ophthalmol; 1985.
20. Zhang Q, Baldwin VJ, Acland GM, Parshall CJ, Haskel J, Aguirre GD, et al. Photoreceptor dysplasia (pd) in miniature schnauzer dogs: evaluation of candidate genes by molecular genetic analysis. J Hered 1999 Jan-Feb;90(1):57–61. doi: 10.1093/jhered/90.1.57 9987905
21. Jeong M, Han C, Narfstrom K, Awano T, Johnson G, Min M, et al. A phosducin (PDC) gene mutation does not cause progressive retinal atrophy in Korean miniature schnauzers. Animal Genetics 2008;39(4):455–456. doi: 10.1111/j.1365-2052.2008.01735.x 18724412
22. Jeong MB, Park SA, Kim SE, Park YW, Narfstroem K, Kangmoon S. Clinical and Electroretinographic Findings of Progressive Retinal Atrophy in Miniature Schnauzer Dogs of South Korea. Journal of Veterinary Medical Science 2013;75(10):1303–1308. doi: 10.1292/jvms.12-0358 23719750
23. Murgiano L, Becker D, Torjman D, Niggel JK, Milano A, Cullen C, et al. Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration. G3 (Bethesda) 2018 Dec 12.
24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001;25(4):402–408. doi: 10.1006/meth.2001.1262 11846609
25. Lizio M, Harshbarger J, Shimoji H, Severin J, Kasukawa T, Sahin S, et al. Gateways to the FANTOM5 promoter level mammalian expression atlas. Genome Biol 2015 Jan 5;16:22-014-0560-6.
26. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536(7616):285. doi: 10.1038/nature19057 27535533
27. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature 2012;489(7414):75. doi: 10.1038/nature11232 22955617
28. Forrest AR, Kawaji H, Rehli M, Baillie JK, De Hoon MJ, Haberle V, et al. A promoter-level mammalian expression atlas. Nature 2014;507(7493):462. doi: 10.1038/nature13182 24670764
29. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015 Jan 23;347(6220):1260419. doi: 10.1126/science.1260419 25613900
30. Liskova P, Dudakova L, Evans CJ, Lopez KER, Pontikos N, Athanasiou D, et al. Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. The American Journal of Human Genetics 2018;102(3):447–459. doi: 10.1016/j.ajhg.2018.02.002 29499165
31. Parshall CJ, Wyman M, Nitroy S, Acland GM, Aguirre GD. Photoreceptor dysplasia: an inherited progressive retinal atrophy of miniature schnauzer dogs. Progress in Veterinary & Comparative Ophthalmology 1991;1(3):187.
32. Rattner A, Nathans J. The genomic response to retinal disease and injury: evidence for endothelin signaling from photoreceptors to glia. Journal of Neuroscience 2005;25(18):4540–4549. doi: 10.1523/JNEUROSCI.0492-05.2005 15872101
33. Bridges PJ, Jo M, Al Alem L, Na G, Su W, Gong MC, et al. Production and binding of endothelin-2 (EDN2) in the rat ovary: endothelin receptor subtype A (EDNRA)-mediated contraction. Reprod Fertil Dev 2010;22(5):780–787. doi: 10.1071/RD09194 20450830
34. Choi D, Kim EK, Kim K, Lee K, Kang D, Kim HY, et al. Expression pattern of endothelin system components and localization of smooth muscle cells in the human pre-ovulatory follicle. Human reproduction 2011;26(5):1171–1180. doi: 10.1093/humrep/der066 21406445
35. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest 2011 Apr;121(4):1429–1444. doi: 10.1172/JCI44646 21383504
36. Bramall AN, Szego MJ, Pacione LR, Chang I, Diez E, D'Orleans-Juste P, et al. Endothelin-2-mediated protection of mutant photoreceptors in inherited photoreceptor degeneration. PLoS One 2013;8(2):e58023. doi: 10.1371/journal.pone.0058023 23469133
37. Rattner A, Yu H, Williams J, Smallwood PM, Nathans J. Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis. Proc Natl Acad Sci U S A 2013 Oct 1;110(40):E3830–9. doi: 10.1073/pnas.1315509110 24043815
38. Samardzija M, Wariwoda H, Imsand C, Huber P, Heynen SR, Gubler A, et al. Activation of survival pathways in the degenerating retina of rd10 mice. Exp Eye Res 2012;99:17–26. doi: 10.1016/j.exer.2012.04.004 22546314
39. Baker S, Booth C, Fillman C, Shapiro M, Blair MP, Hyland JC, et al. A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. American Journal of Medical Genetics Part A 2011;155(7):1668–1672.
40. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics 2007;81(3):559–575. doi: 10.1086/519795 17701901
41. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009 Jul 15;25(14):1754–1760. doi: 10.1093/bioinformatics/btp324 19451168
42. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010 Sep;20(9):1297–1303. doi: 10.1101/gr.107524.110 20644199
43. Gardner EJ, Lam VK, Harris DN, Chuang NT, Scott EC, Pittard WS, et al. The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. Genome Res 2017 Nov;27(11):1916–1929. doi: 10.1101/gr.218032.116 28855259
44. Jurka J, Kapitonov VV, Pavlicek A, Klonowski P, Kohany O, Walichiewicz J. Repbase Update, a database of eukaryotic repetitive elements. Cytogenet Genome Res 2005;110(1–4):462–467. doi: 10.1159/000084979 16093699
45. Layer RM, Kindlon N, Karczewski KJ, Quinlan AR, Exome Aggregation Consortium. Efficient genotype compression and analysis of large genetic-variation data sets. Nature methods 2015;13(1):63. doi: 10.1038/nmeth.3654
46. Koressaar T, Remm M. Enhancements and modifications of primer design program Primer3. Bioinformatics 2007 May 15;23(10):1289–1291. doi: 10.1093/bioinformatics/btm091 17379693
47. Khan A, Fornes O, Stigliani A, Gheorghe M, Castro-Mondragon JA, van der Lee R, et al. JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res 2017;46(D1):D260–D266.
48. Tan G, Lenhard B. TFBSTools: an R/bioconductor package for transcription factor binding site analysis. Bioinformatics 2016;32(10):1555–1556. doi: 10.1093/bioinformatics/btw024 26794315
49. Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res 2017;46(D1):D754–D761.
50. Islam S, Kjallquist U, Moliner A, Zajac P, Fan JB, Lonnerberg P, et al. Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq. Genome Res 2011 Jul;21(7):1160–1167. doi: 10.1101/gr.110882.110 21543516
51. Islam S, Zeisel A, Joost S, La Manno G, Zajac P, Kasper M, et al. Quantitative single-cell RNA-seq with unique molecular identifiers. Nat Methods 2014 Feb;11(2):163–166. doi: 10.1038/nmeth.2772 24363023
52. Krjutskov K, Koel M, Roost AM, Katayama S, Einarsdottir E, Jouhilahti EM, et al. Globin mRNA reduction for whole-blood transcriptome sequencing. Sci Rep 2016 Aug 12;6:31584. doi: 10.1038/srep31584 27515369
53. Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc 2016 Sep;11(9):1650–1667. doi: 10.1038/nprot.2016.095 27560171
54. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15(12):550-014-0550-8.
55. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 2016 Sep 15;32(18):2847–2849. doi: 10.1093/bioinformatics/btw313 27207943
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