Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP

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Qihong Zhang1, Joseph C Giacalone2, Charles Searby3

  • 1Department of Pediatrics, University of Iowa, Iowa City, IA 52242; qihong-zhang@uiowa.edu val-sheffield@uiowa.edu.

Proceedings of the National Academy of Sciences of the United States of America
|January 10, 2019
PubMed

Insights

Mutations in the RPGR gene cause X-linked retinitis pigmentosa (XLRP). This study reveals how RPGR protein interactions are disrupted by mutations, providing an assay to test variant pathogenicity for inherited retinal disease.

Area of Science:

  • Genetics
  • Ophthalmology
  • Molecular Biology

Background:

  • Retinitis pigmentosa (RP) is a group of inherited retinal diseases causing vision loss.
  • Mutations in the RPGR gene are a significant cause of X-linked RP (XLRP).
  • The molecular mechanisms underlying RPGR-associated photoreceptor dysfunction remain unclear.

Purpose of the Study:

  • To investigate the interactions of RPGR isoforms with key cellular proteins.
  • To understand how RPGR mutations affect these interactions and protein localization.
  • To develop a functional assay for evaluating the pathogenicity of RPGR variants.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Analysis of RPGR isoform localization in cultured cells.
  • Evaluation of specific RPGR missense variants, including M58K, in patient-derived cells.
  • Development of an in vitro assay for variant pathogenicity assessment.

Main Results:

  • Both RPGR1-19 and RPGRORF15 isoforms interact with PDE6D, INPP5E, and RPGRIP1L.
  • The C-terminal prenylation site of RPGR1-19 is crucial for its interaction with PDE6D, INPP5E, and RPGRIP1L.
  • RPGR1-19 localizes to cilia, and disease-associated missense variations disrupt these interactions and ciliary localization.
  • A specific variant (M58K) found in XLRP patients disrupts RPGR interactions and ciliary localization.

Conclusions:

  • RPGR protein interactions and ciliary localization are vital for photoreceptor function.
  • Disease-causing RPGR mutations disrupt these critical molecular processes.
  • An in vitro assay has been established to functionally validate RPGR missense variants, aiding in the diagnosis of inherited retinal diseases.
Keywords:
INPP5EPDE6DRPGRciliaretinal degeneration

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