Human induced pluripotent stem cells as a tool to model a form of Leber congenital amaurosis

Cell Reprogram. 2013 Jun;15(3):233-46. doi: 10.1089/cell.2012.0076. Epub 2013 May 10.


Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA) and to model this type of LCA for drug screening. Fibroblasts from two unrelated clinically identified patients with a yet undetermined gene mutation were reprogrammed to pluripotency by retroviral transduction. These human induced pluripotent stem cells (hiPSCs) were differentiated into neural stem cells (NSCs) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome-wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip(®), comparing LCA-hiPSCs derivatives to controls. A genomic search for alteration in all genes known to be involved in LCA revealed a common polymorphism on the GUCY2D gene, referenced as the LCA type I (OMIM *600179 and #204000), but the causative gene remained unknown. The hiPSCs expressed the key pluripotency factors and formed embryoid bodies in vitro containing cells originating from all three germ layers. They were successfully differentiated into NSC and RPE cells. One gene, NNAT, was upregulated in LCA cell populations, and three genes were downregulated, GSTT1, TRIM61 and ZNF558, with potential correlates for molecular mechanisms of this type of LCA, in particular for protein degradation and oxidative stress. The two LCA patient-specific iPSC lines will contribute to modeling LCA phenotypes and screening candidate drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cells, Cultured
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Genome-Wide Association Study
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism
  • Humans
  • In Vitro Techniques
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Leber Congenital Amaurosis / genetics*
  • Leber Congenital Amaurosis / metabolism
  • Leber Congenital Amaurosis / pathology*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Polymorphism, Genetic / genetics*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Up-Regulation


  • DNA-Binding Proteins
  • Membrane Proteins
  • NNAT protein, human
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • TRIM61 protein, human
  • ZNF558 protein, human
  • guanylate cyclase 1
  • glutathione S-transferase T1
  • Glutathione Transferase
  • Guanylate Cyclase