Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice

J Clin Invest. 2008 Aug;118(8):2908-16. doi: 10.1172/JCI35891.

Abstract

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Publication types

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

MeSH terms

  • AC133 Antigen
  • Actin Cytoskeleton / metabolism
  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Electroretinography
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Humans
  • Macular Degeneration / genetics*
  • Macular Degeneration / physiopathology
  • Mice
  • Mice, Transgenic
  • Morphogenesis
  • Mutation, Missense*
  • Nerve Tissue Proteins / metabolism
  • Peptides / genetics*
  • Peptides / metabolism
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Photoreceptor Cells, Vertebrate / ultrastructure

Substances

  • AC133 Antigen
  • Antigens, CD
  • CDHR1 protein, human
  • Cadherins
  • Glycoproteins
  • Nerve Tissue Proteins
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse