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T. Gorgels, G. L. Scheffer, J. D. Meeldijk, A. A. B. Bergen; Disruption of Abcc6 in the Mouse Leads to Calcification in Bruch’s Membrane. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2993.
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Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of connective tissue in eye (Bruch's membrane), skin, heart and blood vessels. The disease is caused by loss of function mutations in ABCC6. To study the role of ABCC6 in PXE pathophysiology, Abcc6 was inactivated in the mouse.
An Abcc6 knockout mouse was generated by targeted disruption of Abcc6 in ES cells. Mice of various ages were sacrificed for analysis by light and electron microscopy. ABCC6 tissue distribution was examined with monoclonal antibodies against mouse ABCC6.
Von Kossa staining showed that Abcc6-/- mice spontaneously developed calcification of blood vessels. This was first noticed in small arteries of the kidney of 3 months old Abcc6-/- mice, but progressively involved other blood vessels and organs as well.Abcc6-/- mice of one year and older also showed changes in Bruch's membrane: Electron microscopy revealed increased electron-density in the elastic as well as in the collagenous layers. EDX (Energy Dispersive X-ray) analysis demonstrated elevated levels of Ca, P and O in these layers. Some of these electron-dense structures had a banding pattern with periodicity of about 55 nm, which suggest that they represent calcified collagen fibers. At 24 months of age, Bruch's membrane stained positive with von Kossa.Immunohistochemistry in wild type mice localized ABCC6 protein in liver and kidney but not in the eye nor at other sites of PXE pathology.
ABCC6 deficiency in the mouse causes calcification of Bruch's membrane, probably affecting both elastic and collagen fibers.
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