Defining the pathogenicity of optineurin in juvenile open-angle glaucoma

Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3122-30. doi: 10.1167/iovs.04-0107.


Purpose: Juvenile open-angle glaucoma (JOAG) differs from primary open-angle glaucoma in that it is usually a more severe phenotype and has an earlier age of onset. Optineurin was recently associated with a variant of POAG that is characterized by intraocular pressure within normal limits: normal-tension glaucoma. The present study tested whether OPTN sequence changes play a role in early-onset glaucoma characterized by elevated intraocular pressure.

Methods: Sixty-six patients with JOAG characterized by high intraocular pressure were screened for mutations. Mutational analysis was performed with a combination of restriction enzyme digestion, single-strand conformation polymorphism, and direct sequencing. The effects of select changes on exon splicing were assessed using bioinformatic modeling approaches and RT-PCR.

Results: Ten sequence changes were identified, of which H486R was strongly suggestive of pathogenicity. H486R represents the first reported OPTN mutation associated with JOAG. Also, L41L is proposed to confer an increased susceptibility to the development of JOAG. Most of the other sequence changes observed were not thought to be biologically significant. The frequency of the previously reported M98K allele was not increased in the JOAG population studied but showed the previously reported skewed distribution in the POAG study population. The changes identified were not shown to affect the splicing machinery.

Conclusions: The results of this work support the hypothesis that mutations in OPTN are not specifically associated with low-pressure glaucoma, but can play a role in JOAG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Arginine
  • Base Sequence
  • Cell Cycle Proteins
  • Child
  • Computational Biology
  • DNA / analysis
  • Female
  • Genome, Human
  • Genotype
  • Glaucoma, Open-Angle / genetics*
  • Glaucoma, Open-Angle / physiopathology
  • Histidine
  • Humans
  • Intraocular Pressure*
  • Leucine
  • Lysine
  • Male
  • Membrane Transport Proteins
  • Methionine
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Transcription Factor TFIIIA / genetics*
  • Transcription, Genetic
  • Visual Fields


  • Cell Cycle Proteins
  • Membrane Transport Proteins
  • OPTN protein, human
  • Transcription Factor TFIIIA
  • Histidine
  • DNA
  • Arginine
  • Methionine
  • Leucine
  • Lysine