The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis

Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3965-70. doi: 10.1073/pnas.0637349100. Epub 2003 Mar 21.


Retinitis pigmentosa is a photoreceptor degenerative disease leading to blindness in adulthood. Leber congenital amaurosis (LCA) describes a more severe condition with visual deficit in early childhood. Defects in the retinitis pigmentosa GTPase regulator (RPGR) and an RPGR-interacting protein (RPGRIP) are known causes of retinitis pigmentosa and LCA, respectively. Both proteins localize in the photoreceptor connecting cilium (CC), a thin bridge linking the cell body and the light-sensing outer segment. We show that RPGR is absent in the CC of photoreceptors lacking RPGRIP, but not vice versa. Mice lacking RPGRIP elaborate grossly oversized outer segment disks resembling a cytochalasin D-induced defect and have a more severe disease than mice lacking RPGR. Mice lacking both proteins are phenotypically indistinguishable from mice lacking RPGRIP alone. In vitro, RPGRIP forms homodimer and elongated filaments via interactions involving its coiled-coil and C-terminal domains. We conclude that RPGRIP is a stable polymer in the CC where it tethers RPGR and that RPGR depends on RPGRIP for subcellular localization and normal function. Our data suggest that RPGRIP is also required for disk morphogenesis, putatively by regulating actin cytoskeleton dynamics. The latter hypothesis may be consistent with a distant homology between the C-terminal domain of RPGRIP and an actin-fragmin kinase, predicted by fold recognition algorithms. A defect in RPGRIP encompasses loss of both functions, hence the more severe clinical manifestation as LCA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Chlorocebus aethiops
  • Cytoskeletal Proteins
  • DNA Primers
  • Exons
  • Eye Proteins*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Morphogenesis / genetics
  • Optic Disk / embryology*
  • Phenotype
  • Photoreceptor Cells, Vertebrate / physiology
  • Polymerase Chain Reaction
  • Proteins / genetics*
  • Proteins / metabolism
  • Recombinant Proteins / metabolism
  • Retinitis Pigmentosa / genetics
  • Saccharomyces cerevisiae / genetics
  • Transfection


  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA Primers
  • Eye Proteins
  • Proteins
  • RPGR protein, human
  • RPGRIP1 protein, human
  • Recombinant Proteins