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Transgenic TBK1 mice have features of normal tension glaucoma.
Fingert, John H; Miller, Kathy; Hedberg-Buenz, Adam; Roos, Ben R; Lewis, Carly J; Mullins, Robert F; Anderson, Michael G.
Afiliação
  • Fingert JH; Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • Miller K; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
  • Hedberg-Buenz A; Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • Roos BR; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
  • Lewis CJ; Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • Mullins RF; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
  • Anderson MG; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA and.
Hum Mol Genet ; 26(1): 124-132, 2017 01 01.
Article em En | MEDLINE | ID: mdl-28025332
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Ganglionares da Retina / Glaucoma / Proteínas Serina-Treonina Quinases / Modelos Animais de Doenças Limite: Animals / Female / Humans / Male Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Ganglionares da Retina / Glaucoma / Proteínas Serina-Treonina Quinases / Modelos Animais de Doenças Limite: Animals / Female / Humans / Male Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos