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Megalin-deficiency causes high myopia, retinal pigment epithelium-macromelanosomes and abnormal development of the ciliary body in mice.

Abstract
In man, mutations of the megalin-encoding gene causes the rare Donnai-Barrow/Facio-Oculo-Acoustico-Renal Syndrome, which is partially characterized by high-grade myopia. Previous studies of renal megalin function have established that megalin is crucial for conservation of renal filtered nutrients including vitamin A; however, the role of megalin in ocular physiology and development is presently unknown. Therefore, we investigate ocular megalin expression and the ocular phenotype of megalin-deficient mice. Topographical and subcellular localization of megalin as well as the ocular phenotype of megalin-deficient mice were examined with immunological techniques using light, confocal and electron microscopy. We identified megalin in the retinal pigment epithelium (RPE) and non-pigmented ciliary body epithelium (NPCBE) in normal mouse eyes. Immunocytochemical investigations furthermore showed that megalin localizes to vesicular structures in the RPE and NPCBE cells. Histological investigations of ocular mouse tissue also identified a severe myopia phenotype as well as enlarged RPE melanosomes and abnormal ciliary body development in the megalin-deficient mice. In conclusion, the complex ocular phenotype observed in the megalin-deficient mice suggests that megalin-mediated developmental abnormalities may contribute to the high myopia phenotype observed in the Donnai-Barrow Syndrome patients and, thus, that megalin harbors important roles in ocular development and physiology. Finally, our data show that megalin-deficient mice may provide a valuable model for future studies of megalin in ocular physiology and pathology.
AuthorsTina Storm, Steffen Heegaard, Erik I Christensen, Rikke Nielsen
JournalCell and tissue research (Cell Tissue Res) Vol. 358 Issue 1 Pg. 99-107 (Oct 2014) ISSN: 1432-0878 [Electronic] Germany
PMID24980834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
Topics
  • Agenesis of Corpus Callosum (genetics, metabolism, pathology)
  • Animals
  • Ciliary Body (metabolism, pathology)
  • Gene Expression Regulation
  • Hearing Loss, Sensorineural (genetics, metabolism, pathology)
  • Hernias, Diaphragmatic, Congenital (genetics, metabolism, pathology)
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-2 (biosynthesis, genetics)
  • Male
  • Melanosomes (genetics, metabolism, pathology)
  • Mice
  • Mice, Mutant Strains
  • Myopia (genetics, metabolism, pathology)
  • Proteinuria (genetics, metabolism, pathology)
  • Renal Tubular Transport, Inborn Errors (genetics, metabolism, pathology)
  • Retinal Pigment Epithelium (metabolism, pathology)

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