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Molecular and Cellular Biology, November 2001, p. 7707-7713, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7707-7713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Byong Su Kim,1 Olga V. Savinova,2 Mark V. Reedy,1 Janice Martin,2 Yi Lun,1 Lin Gan,1,3 Richard S. Smith,2,4 Stanislav I. Tomarev,5 Simon W. M. John,2,4,6 and Randy L. Johnson1,7,*

Department of Biochemistry and Molecular Biology1 and Program in Genes and Development,7 University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030; The Jackson Laboratory2 and The Howard Hughes Medical Institute,4 Bar Harbor, Maine 04609; Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 208925; Department of Ophthalmology Tufts University School of Medicine, Boston, Massachusetts 021116; and Center for Aging and Developmental Biology, University of Rochester, Rochester, New York 146423

Received 4 April 2001/Returned for modification 10 July 2001/Accepted 6 August 2001

Glaucoma 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 GLC1A locus 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 that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-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.

* Corresponding author. Mailing address: Box 117, Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030. Phone: (713) 792-2551. Fax: (713) 791-9478. E-mail: rjohnson{at}odin.mdacc.tmc.edu.

Molecular and Cellular Biology, November 2001, p. 7707-7713, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7707-7713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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