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Molecular and Cellular Biology, October 2004, p. 9019-9025, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9019-9025.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

Douglas B. Gould,1 Laura Miceli-Libby,1 Olga V. Savinova,1,2 Mario Torrado,3 Stanislav I. Tomarev,3 Richard S. Smith,1,2 and Simon W. M. John1,2,4*

The Jackson Laboratory,1 The Howard Hughes Medical Institute, Bar Harbor, Maine,2 Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland,3 Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts4

Received 9 April 2004/ Returned for modification 26 June 2004/ Accepted 2 July 2004

Despite the importance of MYOC for glaucoma, the protein's normal function(s) and the pathogenic mechanism(s) of MYOC mutations are not clear. Elevated intraocular pressure (IOP) and glaucoma are sometimes induced by corticosteroids, and corticosteroid use can result in substantially increased MYOC expression. It has been suggested, therefore, that steroid-induced MYOC protein levels cause steroid-induced glaucoma and that protein level-increasing mutations in MYOC contribute to glaucoma not associated with steroid use. A causative role of elevated MYOC levels in steroid-induced glaucoma is controversial, however, and it is not clear if elevated MYOC levels can result in IOP elevation. To directly test if increased levels of MYOC can cause IOP elevation and glaucoma, we generated bacterial artificial chromosome transgenic mice that overexpress Myoc at a level similar to that induced by corticosteroid use. These mice do not develop elevated IOP or glaucoma. Our present findings, along with the absence of glaucoma in mice completely lacking MYOC, show that changing the level of MYOC is not pathogenic (from absent to approximately 15 times normal). These findings suggest that noncoding sequence variants are unlikely to influence glaucoma and that disease pathogenesis in primary open-angle glaucoma patients is dependent upon the expression of abnormal mutant proteins. This work does not support a causative role for increased MYOC levels or the MYOC gene in steroid-induced glaucoma.

* Corresponding author. Mailing address: The Howard Hughes Medical Institute, 600 Main St., Bar Harbor, Maine. Phone: (207) 288-6000. Fax: (207) 288-6079. E-mail: swmj{at}jax.org.

Molecular and Cellular Biology, October 2004, p. 9019-9025, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.9019-9025.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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