July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Loss of the Peripherin-2/rds (P/rds) C-terminal Domain Causes Progressive Retinal Degeneration in a New Mouse Model of Human Retinal Disease.
Author Affiliations & Notes
  • Breyanna Lynn Cavanaugh
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Michelle Lynn Milstein
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Adam C Seidel
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Mario Hanna
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Sharon X Tan
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Andrew F X Goldberg
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Footnotes
    Commercial Relationships   Breyanna Cavanaugh, None; Michelle Milstein, None; Adam Seidel, None; Mario Hanna, None; Sharon Tan, None; Andrew Goldberg, None
  • Footnotes
    Support  R01EY025291
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 438. doi:
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      Breyanna Lynn Cavanaugh, Michelle Lynn Milstein, Adam C Seidel, Mario Hanna, Sharon X Tan, Andrew F X Goldberg; Loss of the Peripherin-2/rds (P/rds) C-terminal Domain Causes Progressive Retinal Degeneration in a New Mouse Model of Human Retinal Disease.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):438.

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

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Abstract

Purpose : Defects in peripherin-2/rds (P/rds), an integral membrane protein essential for proper formation of the outer segment (OS) membranes of rod and cone photoreceptors, are known to cause a broad variety of inherited retinal diseases. A nonsense mutation at residue 285, which is predicted to truncate the protein’s C-terminus, is associated with macular disease in humans. To investigate the mechanism(s) underlying the role of the P/rds C-terminus in this pathology, we generated and are phenotyping a gene-edited mouse model. This study will further explain how mutations in P/rds cause retinal degeneration (RD) and expand our insight into P/rds structure, function and the normal role of its C-terminus.

Methods : We created P/rds Y285stop knock-in mice (via CRISPR/Cas9) to model a pathogenic mutation associated with humans macular disease. RD was assessed in age-matched (P21 to 9M) Y285stop (+/- and -/-) mice, as compared to C57BL/6J (WT) and rds mutant (+/- and -/-) mice. Hematoxylin and eosin staining was performed on paraffin sections collected from the vertical meridian of the central retina. Outer nuclear layer (ONL) thickness was measured and plotted using Spidergrams to assess RD.

Results : Y285stop +/- mice developed a relatively normal number of photoreceptors (~10% reduction) compared to WT, but progressively lost ~60% of their photoreceptors over 9M. The degeneration rate roughly paralleled that observed in rds +/- mice. Y285stop -/- mice developed ~30% fewer photoreceptors at P21 (relative to WT) and lost up to ~90% by 9M. Similar to the heterozygous mice, the degeneration rate of Y285stop -/- mice roughly paralleled that observed in rds -/- mice.

Conclusions : A Y285stop mutation in P/rds associated with human macular disease led to dramatic and progressive retinal degeneration in mice. This model demonstrates that the C-terminus is indispensable for P/rds support of photoreceptor structure and the maintenance of retinal health. We further establish that the photoreceptor degeneration rate in this model shows a gene dosage effect roughly comparable to that observed in the rds mouse. Comprehensive phenotyping of the new model will include IHC, TEM, Western blotting, and ERG analyses, and will assess whether Y285stop has a preferential effect on cone photoreceptor function and viability.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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