Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma

Hum Mol Genet. 2004 Jun 1;13(11):1193-204. doi: 10.1093/hmg/ddh128. Epub 2004 Apr 6.


Glaucoma is a progressive blinding disease characterized by gradual loss of vision due to optic neuropathy and retinal ganglion cell death. Increased intraocular pressure is a common feature of glaucoma that is thought to arise from an increased resistance to outflow of aqueous humor through the trabecular meshwork. Mutations of the myocilin gene are one cause of autosomal dominant juvenile- and adult-onset primary open angle glaucoma, but the mechanism by which mutant myocilins cause disease is poorly understood. We have found that disease-causing myocilin mutants are misfolded, are highly aggregation-prone and accumulate in large aggregates in the endoplasmic reticulum (ER) of human embryonic kidney cells and differentiated primary human trabecular meshwork (HTM) cells. In HTM cells, Pro370Leu mutant myocilin is not secreted under normal culture conditions and prolonged expression results in abnormal cell morphology and cell killing. Culturing HTM cells at 30 degrees C, a condition known to facilitate protein folding, promotes secretion of mutant myocilin, normalizes cell morphology and reverses cell lethality. Our results indicate that myocilin-associated glaucoma is an ER storage disease and suggest a progression of events in which chronic expression of misfolded, non-secreted myocilin leads to HTM cell death, trabecular meshwork dysfunction and, ultimately, a dominant glaucoma phenotype. The beneficial effects of facilitating folding and secretion of mutant myocilin suggest a new type of treatment for this form of glaucoma.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Calnexin / metabolism
  • Calreticulin / metabolism
  • Cell Extracts / analysis
  • Cell Line
  • Cell Survival
  • Cysteine Endopeptidases / metabolism
  • Cytoskeletal Proteins
  • Detergents / chemistry
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Eye Proteins / chemistry
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Genetic Vectors
  • Glaucoma / diet therapy
  • Glaucoma / genetics*
  • Glycoproteins / chemistry
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Humans
  • Intranuclear Inclusion Bodies / ultrastructure
  • Microscopy, Fluorescence
  • Multienzyme Complexes / metabolism
  • Mutation, Missense*
  • Precipitin Tests
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Folding
  • Temperature
  • Transfection


  • Calreticulin
  • Cell Extracts
  • Cytoskeletal Proteins
  • Detergents
  • Eye Proteins
  • Glycoproteins
  • Multienzyme Complexes
  • trabecular meshwork-induced glucocorticoid response protein
  • Calnexin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex