title: Transgenic TBK1 mice have features of normal tension glaucoma.
abstract: Duplication of the TBK1 gene is associated with 1-2% of normal tension glaucoma, a common cause of vision loss and blindness that occurs without grossly abnormal intraocular pressure. We generated a transgenic mouse that has one copy of the human TBK1 gene (native promoter and gene structure) incorporated into the mouse genome (Tg-TBK1). Expression of the TBK1 transgene in the retinae of these mice was demonstrated by real-time PCR. Using immunohistochemistry TBK1 protein was predominantly localized to the ganglion cell layer of the retina, the cell type most affected by glaucoma. More intense TBK1 labelling was detected in the retinal ganglion cells (RGCs) of Tg-TBK1 mice than in wild-type littermates. Tg-TBK1 mice exhibit the cardinal sign of glaucoma, a progressive loss of RGCs. Hemizygous Tg-TBK1 mice (with one TBK1 transgene per genome) had a 13% loss of RGCs by 18 months of age (P = 1.5 × 10-8). Homozygous Tg-TBK1 mice had 7.6% fewer RGCs than hemizygous Tg-TBK1 mice and 20% fewer RGCs than wild-type mice (P = 1.9 × 10-5) at 6 months of age. No difference in intraocular pressures was detected between Tg-TBK1 mice and wild-type littermates as they aged (P > 0.05). Tg-TBK1 mice with extra doses of the TBK1 gene recapitulate the phenotype of normal tension glaucoma in human patients with a TBK1 gene duplication. Together, these studies confirm the pathogenicity of the TBK1 gene duplication in human glaucoma and suggest that excess production of TBK1 kinase may have a role in the pathology of glaucoma.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Fingert
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.|Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and.
authors.forename: Adam
authors.initials: A
authors.lastname: Hedberg-Buenz
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
authors.forename: Ben R
authors.initials: BR
authors.lastname: Roos
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.|Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and.
authors.forename: Carly J
authors.initials: CJ
authors.lastname: Lewis
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.|Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and.|VA Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human