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M. Bustamante, A. Tasinato, F. Maurer, M. Lepore, Y. Arsenijevic, T. Pedrazzini, F. L. Munier, D. F. Schorderet; Overexpression of Mutant Forms of TGFBI/BIGH3 Gene Causing Corneal Dystrophy Induces Retinal Degeneration in vivo. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5861.
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Specific mutations in the Transforming Growth Factor beta-induced gene BIGH3 have been associated with corneal dystrophies. In patients this is correlated with immuno-reactive deposits of keratoepithelin (KE) the product of BIGH3. Despite the ubiquitous expression of the encoded KE, no other deposit has been described in tissues other than the cornea. Our aim is to investigate the role of BIGH3 by generating an in vivo mouse overexpressing mutated forms of BIGH3.
Using lentiviral vectors, we generated transgenic mice lines expressing human BigH3 containing the R555W mutation under the control of the mouse PGK-1, and the R124C mutation under the control of the human ubiquitin C promoter. Transgenic founders were cross-bred for several generations in order to establish a stable line. Expression of the transgene was monitored by western blot analysis using a polyclonal antibody against KE. ERG was performed and compared to age matched controls. Mice were sacrified and subjected to targeted necroscopy of all organs and extensive hematoxylin-eosin analysis, X-ray and physiological investigation.
We observed transgenic expression in different organs, without specific transgene expression in the cornea. Overall morphology of the transgenic animals did not appear to be affected by KE expression. Still, we observed follicular hyperplasia in the spleen and lipofuscin expression in the adrenal gland in female transgenic animals, suggesting a possible accelerated aging process. The relative weight of the kidney appeared to be consistently increased, but organ morphology was normal. Interestingly, transgene expression caused an age dependent retinal degeneration, associated with significant attenuation of cone response and rod ERG amplitudes.
We generated transgenic lines expressing human BIGH3 containing the two classical mutations. Extensive pathological analysis showed cellular degeneration in the retina of transgenic animals, with concomitant ERG amplitudes attenuation in aged mice or an early death of overexpressing cells. No phenotype could be observed in the cornea, probably due to the lack of transgene expression. Females also displayed an apparent follicular hyperplasia in the spleen and accelerated aging signs in the adrenal gland.
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