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Targeted Disruption of the Myocilin Gene ( Myoc ) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function

2001; Taylor & Francis; Volume: 21; Issue: 22 Linguagem: Inglês

10.1128/mcb.21.22.7707-7713.2001

1098-5549

Byong Su Kim, О. В. Савинова, Mark V. Reedy, Janice E Martin, Yi Lun, Lin Gan, Richard S. Smith, Stanislav I. Tomarev, Simon W. M. John, Randy L. Johnson,

Corneal surgery and disorders

AbstractGlaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1Alocus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate thatMyoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in bothMyoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function. ACKNOWLEDGMENTSWe thank Kenneth Dunner and the M. D. Anderson Cancer Center Electron Microscope Core facility for TEM analysis, Adriana Zabaleta for technical advice and assistance, and Dr. Richard Behringer for helpful comments on the manuscript. B.S.K. thanks former colleagues at Alkermes, Inc., for encouragement.This work was supported in part by M. D. Anderson Cancer Center Core Grants to the veterinary services and Electron Microscope and DNA Sequencing core facilities, an NIH predoctoral training grant (EY0702420) to B.S.K., an NIH postdoctoral training grant (5F32EY06945) to M.V.R., and an NIH grant (EY123113) to R.L.J. S.W.M.J. is an Assistant Investigator of the Howard Hughes Medical Institute.