Skip to main content
SpringerLink
Log in

Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber’s Congenital Amaurosis

  • Protocol
  • First Online:
Mouse Models for Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1438))

Abstract

Leber’s congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision in the first year of life. In addition to early vision loss, a variety of other eye-related abnormalities including roving eye movements, deep-set eyes, and sensitivity to bright light also occur with this disease. Many animal models of LCA are available and the study them has led to a better understanding of the pathology of the disease, and has led to the development of therapeutic strategies aimed at curing or slowing down LCA. Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human LCA. Such mice provide reproducible, experimental systems for elucidating pathways of normal development, function, designing strategies and testing compounds for translational research and gene-based therapies aimed at delaying the diseases progression. In this chapter, I describe tools used in the discovery and evaluation of mouse models of LCA including a Phoenix Image-Guided Optical Coherence Tomography (OCT) and a Diagnosys Espion Visual Electrophysiology System. Three mouse models are described, the rd3 mouse model for LCA12 and LCA1, the rd12 mouse model for LCA2, and the rd16 mouse model for LCA10.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chung DC, Traboulsi EI (2009) Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS 13:587–592

    Article  PubMed  Google Scholar 

  2. Wang H, Wang X, Zou X, Xu S, Li H, Soens ZT et al (2015) Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort. Invest Ophthalmol Vis Sci 56:3642–3655

    Article  PubMed  PubMed Central  Google Scholar 

  3. Franceschetti A, Dieterle P (1954) Diagnostic and prognostic importance of the electroretinogram in tapetoretinal degeneration with reduction of the visual field and hemeralopia. Confin Neurol 14:184–186

    Article  CAS  PubMed  Google Scholar 

  4. den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27:391–419

    Article  Google Scholar 

  5. Molday LL, Djajadi H, Yan P, Szczygiel L, Boye SL, Chiodo VA et al (2013) RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. Hum Mol Genet 22:3894–3905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Molday LL, Jefferies T, Molday RS (2014) Insights into the role of RD3 in guanylate cyclase trafficking, photoreceptor degeneration, and Leber congenital amaurosis. Front Mol Neurosci 7:44

    Article  PubMed  PubMed Central  Google Scholar 

  7. Azadi S (2013) RD3: a challenge and a promise. JSM Biotechnol Biomed Eng 1:1016

    PubMed  PubMed Central  Google Scholar 

  8. Zheng Q, Ren Y, Tzekov R, Zhang Y, Chen B, Hou J et al (2012) Differential proteomics and functional research following gene therapy in a mousemodel of Leber congenital amaurosis. PLoS One 7:e44855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Burnight ER, Wiley LA, Drack AV, Braun TA, Anfinson KR, Kaalberg EE et al (2014) CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. Gene Ther 21:662–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chang B, Heckenlively JR, Hawes NL, Roderick TH (1993) New mouse primary retinal degeneration (rd-3). Genomics 16:45–49

    Article  CAS  PubMed  Google Scholar 

  11. Danciger JS, Danciger M, Nusinowitz S, Rickabaugh T, Farber DB (1999) Genetic and physical maps of the mouse rd3 locus; exclusion of the ortholog of USH2A. Mamm Genome 10:657–661

    Article  CAS  PubMed  Google Scholar 

  12. Friedman JS, Chang B, Kannabiran C, Chakarova C, Singh HP, Jalali S et al (2006) Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet 79:1059–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Azadi S, Molday LL, Molday RS (2010) RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells. Proc Natl Acad Sci U S A 107:21158–21163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zulliger R, Naash MI, Rajala RV, Molday RS, Azadi S (2015) Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to Leber congenital amaurosis-1. J Biol Chem 290:3488–3499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pang J, Chang B, Hawes NL, Hurd RE, Davisson MT, Li J, Noorwez SM et al (2005) Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol Vis 11:152–162

    CAS  PubMed  Google Scholar 

  16. Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C et al (1997) Mutations in RPE65 cause Leber’s congenital amaurosis. Nat Genet 17:139–141

    Article  CAS  PubMed  Google Scholar 

  17. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci U S A 95:3088–3093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pang J, Chang B, Kumar A, Nusinowitz S, Noorwez SM, Li J, Rani A et al (2006) Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis. Mol Ther 13:565–572

    Article  CAS  PubMed  Google Scholar 

  19. Pang J, Boye SE, Lei B, Boye SL, Everhart D, Ryals R et al (2010) Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency. Gene Ther 17:815–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li X, Li W, Dai X, Kong F, Zeng Q, Zhou X, Lü F, Chang B et al (2011) Gene therapy rescues cone structure and function in the three-month-old rd12 mouse: a model for mid-course RPE65 Leber congenital amaurosis. Invest Ophthalmol Vis Sci 52:7–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ et al (2008) Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A 105:15112–15117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cideciyan AV (2010) Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29:398–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jacobson SG, Cideciyan AV, Ratnakaram R et al (2012) Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 130(1):9–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK et al (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847–1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cideciyan AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK et al (2007) Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum Mutat 28:1074–1083

    Article  CAS  PubMed  Google Scholar 

  26. McEwen DP, Koenekoop RK, Khanna H, Jenkins PM, Lopez I, Swaroop A, Martens JR (2007) Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc Natl Acad Sci U S A 104:15917–15922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Subramanian B, Anand M, Khan NW, Khanna H (2014) Loss of Raf-1 kinase inhibitory protein delays early-onset severe retinal ciliopathy in Cep290rd16 mouse. Invest Ophthalmol Vis Sci 55:5788–5794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Collin RW, den Hollander AI, van der Velde-Visser SD, Bennicelli J, Bennett J, Cremers FP (2012) Antisense oligonucleotide (AON)-based therapy for Leber congenital amaurosis caused by a frequent mutation in CEP290. Mol Ther Nucleic Acids 1:e14

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, Atmaca-Sonmez P, Nusinowitz S, Heckenlively JR (2006) Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci 47:5017–5021

    Article  PubMed  Google Scholar 

  30. Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC et al (2009) A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A 106:19581–19586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chang B, Heckenlively JR, Bayley PR, Brecha NC, Davisson MT, Hawes NL et al (2006) The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11–24

    Article  PubMed  PubMed Central  Google Scholar 

  32. Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S et al (2008) Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. J Physiol 586:4409–4424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chang B, Hawes NL, Hurd RE, Wang J, Howell D, Davisson MT et al (2005) Mouse models of ocular diseases. Vis Neurosci 22:587–593

    Article  CAS  PubMed  Google Scholar 

  34. Won J, Shi LY, Hicks W, Wang J, Hurd R, Naggert JK, Chang B, Nishina PM (2011) Mouse model resources for vision research. J Ophthalmol 2011:391384

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hawes NL, Chang B, Hageman GS, Nusinowitz S, Nishina PM, Schneider BS et al (2000) Retinal degeneration 6(rd 6): a new mouse model for human retinitis punctata albescens. Invest Ophthalmol Vis Sci 41:3149–3157

    CAS  PubMed  Google Scholar 

  36. Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT et al (2007) Two mouse retinal degenerations caused by missense mutations in the “beta”-subunit of rod cGMP phosphodiesterase gene. Vis Res 47:624–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Friedman JS, Chang B, Krauth DS, Lopez I, Waseem NH, Hurd RE et al (2010) Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice. Proc Natl Acad Sci U S A 107:15523–15528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Acland GM, Aguirre GD, Ray J et al (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95

    CAS  PubMed  Google Scholar 

  39. Cideciyan AV, Hauswirth WW, Aleman TS et al (2009) Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 20:999–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maguire AM, High KA, Auricchio A et al (2009) Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374:1597–1605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pawlyk BS, Bulgakov OV, Liu X et al (2010) Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther 21:993–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by the National Eye Institute Grant EY019943 and EY011996. I am grateful to Dr. Patsy Nishina for her critical reading and editing of the manuscript.

Author information

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA

    Bo Chang

Authors
  1. Bo Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bo Chang .

Editor information

Editors and Affiliations

  1. Takeda Pharmaceutical Company, Cambridge, Massachusetts, USA

    Gabriele Proetzel

  2. The Jackson Laboratory, Bar Harbor, Maine, USA

    Michael V. Wiles

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Chang, B. (2016). Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber’s Congenital Amaurosis. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 1438. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3661-8_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3661-8_21

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3659-5

  • Online ISBN: 978-1-4939-3661-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation