May 2006
Volume 47, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2006
Elovl4 5–bp Deletion Knock–In Mice Show Progressive Photoreceptor Degeneration
Author Affiliations & Notes
  • V. Vasireddy
    Ophthalmology and Visual Sciences, W.K Kellogg Eye Center, University Of Michigan, Ann Arbor, MI
  • M.M. Jablonski
    Ophthalmology, UTHSC Hamilton Eye Institute, University Of Tennessee, Memphis, TN
  • M.A. Mandal
    Ophthalmology and Visual Sciences, W.K Kellogg Eye Center, University Of Michigan, Ann Arbor, MI
  • D. Prag
    NIDCD/NEI, National Institute of Health, Bethesda, MD
  • X. Wang
    Ophthalmology and Visual Sciences, UTHSC Hamilton eye Institute, University of Tennessee, Memphis, TN
  • L.M. Niziol
    Ophthalmology and Visual Sciences, W.K Kellogg Eye Center, University Of Michigan, Ann Arbor, MI
  • D.C. Musch
    Ophthalmology and Visual Sciences, W.K Kellogg Eye Center, University Of Michigan, Ann Arbor, MI
  • N. Salem, Jr.
    NIAAA, National Institute of Health, Bethesda, MD
  • P.A. Sieving
    NIDCD/NEI, National Institute of Health, Bethesda, MD
  • R. Ayyagari
    Ophthalmology and Visual Sciences, W.K Kellogg Eye Center, University Of Michigan, Ann Arbor, MI
  • Footnotes
    Commercial Relationships  V. Vasireddy, None; M.M. Jablonski, None; M.A. Mandal, None; D. Prag, None; X. Wang, None; L.M. Niziol, None; D.C. Musch, None; N. Salem, None; P.A. Sieving, None; R. Ayyagari, None.
  • Footnotes
    Support  NIH EY 13198
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4592. doi:
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      V. Vasireddy, M.M. Jablonski, M.A. Mandal, D. Prag, X. Wang, L.M. Niziol, D.C. Musch, N. Salem, Jr., P.A. Sieving, R. Ayyagari; Elovl4 5–bp Deletion Knock–In Mice Show Progressive Photoreceptor Degeneration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4592.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Human autosomal dominant Stargardt–like macular degeneration (STGD3) is associated with a 5–bp deletion(AACTT) mutation in the gene, ELOngation of Very Long chain fatty acid 4 (ELOVL4). This study was designed to generate and characterize a knock–in mouse model with the E lovl4 5–bp deletion (E_mut+/– ).

Methods: : The E_mut+/– mice were generated on C57BL/6 background by targeting the 5–bp deletion in the Elovl4 gene using homologous recombination. Retinal structure and function of 2 to 12 months old E_mut+/– mice and age matched littermate controls were studied by analyzing morphology, ultrastructure, ERG, expression of Elovl4 and photoreceptor specific genes, ELOVL4 protein and retinal fatty acids.

Results: : Presence of both wild type and mutant Elovl4 transcripts was observed in the retinal tissue of E_mut+/– mice. Western blot analysis detected the presence of both forms of the protein. Morphological analysis revealed considerable abnormalities in the photoreceptor layer and accumulation of sub retinal debri. Ultrastructure analysis showed disorganized outer segments, accumulation of partially digested outer segment debri, lipofuscin and melanin granules in the RPE. These morphological changes were found to be progressive over 12 months. Level of expression of selected photoreceptor genes was found to be significantly low in E_mut+/– mice retina by 8 months. Higher a– and b–wave amplitudes were observed in mixed rod–cone as well as cone ERG responses of 8 months old E_mut+/– mice compared to litter mate controls. Levels of 20:5, 22:5 and 24:6 fatty acids were found to be lower (P<0.05) in E_mut+/– retina compared to controls.

Conclusions: : The retinal pathology observed in E_mut+/– mice was progressive with age and showed several features resembling the phenotype observed in STGD3 patients with ELOVL4 5–bp deletion mutation. These animals will serve as a valuable model to understand the mechanism underlying STGD3.

Keywords: retina • retinal degenerations: cell biology • gene/expression 
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