Overexpression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice.
OBJECTIVE
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.
Bustamante
Mauro
M
Institut de Recherche en Ophtalmologie, Sion, Switzerland. mauro.bustamante@irovision.ch
Tasinato
Andrea
A
Maurer
Fabienne
F
Elkochairi
Ilhem
I
Lepore
Mario G
MG
Arsenijevic
Yvan
Y
Pedrazzini
Thierry
T
Munier
Francis L
FL
Schorderet
Daniel F
DF
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D004596:Electroretinography; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006965:Hyperplasia; D016086:Lentivirus; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism*; D009929:Organ Size; D009928:Organ Specificity; D010735:Phosphoglycerate Kinase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012162:Retinal Degeneration / Q000201:enzymology / Q000473:pathology*; D013154:Spleen / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D050505:Mutant Proteins; D010735:Phosphoglycerate Kinase; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein