September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Changes in RDS/Peripherin-2 binding properties and complex formation underlie macular dystrophy
Author Affiliations & Notes
  • Rahel Sarah Zulliger
    Biomedical Engineering, University of Houston, Houston, Texas, United States
  • Shannon M Conley
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Dibyendu Chakraborty
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Michael W Stuck
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Muna I Naash
    Biomedical Engineering, University of Houston, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Rahel Zulliger, None; Shannon Conley, None; Dibyendu Chakraborty, None; Michael Stuck, None; Muna Naash, None
  • Footnotes
    Support  NIH R01 EY10609
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3172. doi:
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    • Get Citation

      Rahel Sarah Zulliger, Shannon M Conley, Dibyendu Chakraborty, Michael W Stuck, Muna I Naash; Changes in RDS/Peripherin-2 binding properties and complex formation underlie macular dystrophy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3172.

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

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Abstract

Purpose : Mutations in the photoreceptor-specific gene RDS/Peripherin-2 have been described in patients with phenotypes from autosomal dominant retinitis pigmentosa to macular dystrophy. Study of the RDS model (rds-/-) has shown that the rod-dominant phenotypes are caused by RDS haploinsufficiency; however, mechanisms for cone-dominant phenotypes remain elusive. We thus evaluated several different knockin models carrying macular dystrophy mutations in RDS.

Methods : We generated lines carrying the K153del, C213Y, Y141C and C150S mutations. Phenotypes were assessed by electroretinography (ERG), histology/EM, fundus imaging and biochemically for levels of mutant RDS and its binding partner ROM-1. RDS/ROM-1 oligomerization was assessed by non-reducing velocity sedimentation and immunoprecipitation (IP).

Results : Mice heterozygous for each of the mutations showed a more severe decrease in cone function than that seen in the rds+/-. However, each model exhibited subtle differences in other outcomes such as fundus phenotype, outer segment (OS) structure, and rod function. Each mutation caused defects in RDS/ROM-1 oligomerization, however the precise defect varied. C213Y RDS loses its ability to bind to ROM-1 completely, while C150S and K153del RDS show decreased ROM-1 binding specifically in cones. When expressed alone (in homozygous animals) C150S, K153del, and C213Y RDS assemble into tetramers, but not the higher-order oligomers required for OS formation. In contrast, Y141C RDS binds ROM-1 and leads to the formation of abnormal large higher-order oligomers. In all cases, the mutant protein traffics properly to the OS in the presence of WT RDS, however, C213Y and K153del RDS, but not C150S or Y141C RDS, mislocalize to the inner segment/outer nuclear layer in the absence of WT RDS.

Conclusions : These data suggest that altered RDS/ROM-1 complex formation coupled with continued OS targeting provides a potential pathogenic mechanism for the cone-dominant retinal degeneration caused by different mutations. In all the lines, the mutations disrupted the complex formation crucial for the function of RDS, leading to the conclusion that cone structure and function are highly sensitive to changes in RDS complexes, while rods are more influenced by changes in the amount of RDS.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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