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Modulating expression of peripherin/rds in transgenic mice: critical levels and the effect of overexpression.

AbstractPURPOSE:
Mutations in the photoreceptor-specific protein peripherin/rds are associated with multiple retinal diseases. To date, attempts to achieve complete structural and functional rescue in animal models of peripherin/rds-induced retinal degeneration have not been successful. Gene therapy-directed approaches have been hindered by the haploinsufficiency phenotype, which dictates well-regulated expression of peripherin/rds protein levels.
METHODS:
Using a transgenic mouse line expressing wild-type peripherin/rds (NMP), the authors evaluated the critical in vivo level of peripherin/rds needed to maintain photoreceptor structure and ERG function and assessed the consequences of peripherin/rds overexpression in both rods and cones by Western blot and immunoprecipitation analyses, immunohistochemistry, electron microscopy, and electroretinography. The NMP transgene included a C-terminal modification (P341Q) to facilitate detection of the transgenic protein in the presence of wild-type peripherin/rds, using the monoclonal antibody 3B6.
RESULTS:
Peripherin/rds protein levels in NMP homozygotes were approximately 60% of wild-type levels. Western blot and immunoprecipitation analyses confirmed normal biochemical properties of the NMP protein when compared with wild-type peripherin/rds. Immunohistochemistry demonstrated appropriate localization of transgenic peripherin/rds protein to the disc rim region of photoreceptor outer segments. Total peripherin/rds levels in the retina were modulated by crossing NMP transgenic mice into different rds genetic backgrounds. A positive correlation was observed between peripherin/rds expression levels and the structural and functional integrity of photoreceptor outer segments. Overexpression of peripherin/rds caused no detectable adverse effects on rod or cone structure and function.
CONCLUSIONS:
These findings may have significant implications regarding therapeutic intervention in peripherin/rds-associated retinal diseases.
AuthorsMay Nour, Xi-Qin Ding, Heidi Stricker, Steven J Fliesler, Muna I Naash
JournalInvestigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 45 Issue 8 Pg. 2514-21 (Aug 2004) ISSN: 0146-0404 [Print] United States
PMID15277471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Intermediate Filament Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Peripherins
  • Prph2 protein, mouse
Topics
  • Animals
  • Blotting, Western
  • Electroretinography
  • Female
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression Regulation (physiology)
  • Immunoblotting
  • Intermediate Filament Proteins (genetics, metabolism)
  • Male
  • Membrane Glycoproteins (genetics, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins (genetics, metabolism)
  • Peripherins
  • Photoreceptor Cells, Vertebrate (metabolism, ultrastructure)
  • Precipitin Tests
  • Retinal Degeneration (metabolism, pathology)

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