Overexpression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice

Autor: Bustamante M, Tasinato A, Maurer F, Elkochairi I, Mg, Lepore, Yvan Arsenijevic, Pedrazzini T, Fl, Munier, Df, Schorderet
Předmět:
Male
Corneal Dystrophies
Virus Integration
Cells
Blotting
Western
Integration
Mice
Transgenic
Animals
Blotting
Southern
Electroretinography
Extracellular Matrix Proteins/genetics
Extracellular Matrix Proteins/metabolism
Female
Gene Expression Regulation
Humans
Hyperplasia
Lentivirus
Mice
Mutant Proteins/metabolism
Organ Size
Organ Specificity
Phosphoglycerate Kinase/genetics
Promoter Regions
Genetic/genetics
RNA
Messenger/genetics
RNA
Messenger/metabolism
Reproducibility of Results
Retinal Degeneration/enzymology
Retinal Degeneration/pathology
Spleen/pathology
Transforming Growth Factor beta/genetics
Transforming Growth Factor beta/metabolism
Kerato-Epithelin Mutations
Transduction
Transforming Growth Factor beta
RNA
Messenger
Promoter Regions
Genetic
Extracellular Matrix Proteins
Retinal Degeneration
eye diseases
Scid-X1
Phosphoglycerate Kinase
Mutant Proteins
sense organs
Therapy
In-Vivo
Spleen
Vivo Gene Delivery
Research Article
Lentiviral Vector
Zdroj: Europe PubMed Central
Molecular Vision, vol. 14, pp. 1129-1137
Molecular Vision
Popis: PURPOSE: Despite ubiquitous expression of the keratoepithelin (KE) protein encoded by the transforming growth factor beta induced/beta induced gene human clone 3 (TGFBI/BIGH3) gene, corneal dystrophies are restricted to the cornea, and no other tissues are affected. We investigated the role of TGFBI/BIGH3 in Groenouw corneal dystrophies by generating transgenic mice overexpressing TGFBI/BIGH3 containing the R555W mutation. METHODS: Transgenic animals expressing the Groenouw mutation of human TGFBI/BIGH3 were generated using lentiviral vectors. The line expressed TGFBI/BIGH3 containing the R555W mutation under the control of the phosphoglycerate kinase (PGK) promoter. Expression of the transgene was monitored by Southern and western blotting and by RT-PCR. Electroretinogram analysis was performed and four mice were subjected to complete necroscopy. RESULTS: Transgene expression was observed in different organs although without specific expression in the cornea. The overall morphology of the transgenic animals was not severely affected by KE overexpression. However, we observed an age-dependent retinal degeneration both functionally and histologically. Female-specific follicular hyperplasia in the spleen and increased levels of lipofuscin in the adrenal gland were also seen in transgenic animals. CONCLUSIONS: Cellular degeneration in the retina of transgenic animals suggest that perturbation of the transforming growth factor beta (TGFbeta) family regulation may affect photoreceptor survival and may induce possible accelerated aging in several tissues. No corneal phenotype could be observed, probably due to the lack of transgene expression in this tissue.
Databáze: OpenAIRE
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