This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gould, D. B.
Right arrow Articles by John, S. W. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gould, D. B.
Right arrow Articles by John, S. W. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2006, p. 8427-8436, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01127-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma{triangledown}

Douglas B. Gould,1 Mark Reedy,2,{dagger} Lawriston A. Wilson,1,3 Richard S. Smith,1,3 Randy L. Johnson,2 and Simon W. M. John1,3,4*

The Jackson Laboratory, Bar Harbor, Maine,1 Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas,2 The Howard Hughes Medical Institute, Bar Harbor, Maine,3 Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts4

Received 22 June 2006/ Returned for modification 19 July 2006/ Accepted 27 August 2006

Glaucoma is a leading cause of blindness, affecting over 70 million people worldwide. Vision loss is the result of death of the retinal ganglion cells. The best-known risk factor for glaucoma is an elevated intraocular pressure (IOP); however, factors leading to IOP elevation are poorly understood. Mutations in the MYOC gene are an important cause of open-angle glaucoma. Over 70 MYOC mutations have been identified, and they lead to approximately 5% of all primary open-angle glaucoma cases. Nevertheless, the pathogenic mechanisms by which these mutations elevate IOP are presently unclear. Data suggest that a dominant interfering effect of misfolded mutant MYOC molecules may be pathogenic. To test this hypothesis, we have generated mice carrying a mutant allele of Myoc that is analogous to a human mutation that leads to aggressive glaucoma in patients. We show that mutant MYOC is not secreted into the aqueous humor. Instead of being secreted, mutant MYOC accumulates within the iridocorneal angle of the eye, consistent with the behavior of abnormally folded protein. Surprisingly, the accumulated mutant protein does not activate the unfolded protein response and lead to elevated intraocular pressure or glaucoma in aged mice of different strains. These data suggest that production, apparent misfolding, and nonsecretion of mutant MYOC are not, by themselves, sufficient to cause glaucoma in vivo.

* Corresponding author. Mailing address: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. Phone: (207) 288-6476. Fax: (207) 288-6079. E-mail: simon.john{at}jax.org.

{triangledown} Published ahead of print on 5 September 2006.

{dagger} Present address: Department of Cell and Developmental Biology, Creighton University, Omaha, NE.

Molecular and Cellular Biology, November 2006, p. 8427-8436, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01127-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jia, L.-Y., Gong, B., Pang, C.-P., Huang, Y., Lam, D. S.-C., Wang, N., Yam, G. H.-F. (2009). Correction of the Disease Phenotype of Myocilin-Causing Glaucoma by a Natural Osmolyte. IOVS 50: 3743-3749 [Abstract] [Full Text]  
  • Hoffman, E. A., Perkumas, K. M., Highstrom, L. M., Stamer, W. D. (2009). Regulation of Myocilin-Associated Exosome Release from Human Trabecular Meshwork Cells. IOVS 50: 1313-1318 [Abstract] [Full Text]  
  • Zhou, Y., Grinchuk, O., Tomarev, S. I. (2008). Transgenic Mice Expressing the Tyr437His Mutant of Human Myocilin Protein Develop Glaucoma. IOVS 49: 1932-1939 [Abstract] [Full Text]  
  • Shepard, A. R., Jacobson, N., Millar, J. C., Pang, I.-H., Steely, H. T., Searby, C. C., Sheffield, V. C., Stone, E. M., Clark, A. F. (2007). Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure. Hum Mol Genet 16: 609-617 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»