title: Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: B S
authors.initials: BS
authors.lastname: Kim
authors.forename: O V
authors.initials: OV
authors.lastname: Savinova
authors.forename: M V
authors.initials: MV
authors.lastname: Reedy
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: Y
authors.initials: Y
authors.lastname: Lun
authors.forename: L
authors.initials: L
authors.lastname: Gan
authors.forename: R S
authors.initials: RS
authors.lastname: Smith
authors.forename: S I
authors.initials: SI
authors.lastname: Tomarev
authors.forename: S W
authors.initials: SW
authors.lastname: John
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods; D005902:Glaucoma, Open-Angle / Q000473:pathology*; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D012333:RNA, Messenger; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D012333:RNA, Messenger; D000099179:Myocilin