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

Abstract

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.

We thank Michael Anderson, Jane Barker, Richard Libby, and John Sundberg for critical review of the manuscript, Jen Smith for work on the figures, and Felicia Farley for assistance with references.

We are supported by the National Eye Institute (grant EY11721 to S.W.M.J.), the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada (D.B.G.), and the National Eye Institute Intramural Program (S.I.T). Scientific support services at The Jackson Laboratory are subsidized by a core grant from the National Cancer Institute (CA34196). S.W.M.J. is an Associate Investigator of The Howard Hughes Medical Institute.