title: Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum.
abstract: Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue, affecting mainly skin, eye and the cardiovascular system. PXE is characterized by dystrophic mineralization of elastic fibres. The condition is caused by loss of function mutations in ABCC6. We generated Abcc6 deficient mice (Abcc6-/-) by conventional gene targeting. As shown by light and electron microscopy Abcc6-/- mice spontaneously developed calcification of elastic fibres in blood vessel walls and in Bruch's membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Newly developed monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6-/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. We conclude that the phenotype of the Abcc6-/- mouse shares calcification of elastic fibres with human PXE pathology, which makes this model a useful tool to further investigate the aetiology of PXE. Our data support the hypothesis that PXE is in fact a systemic disease.
authors.affiliation: Department of Molecualr and Clinical Ophthalmogenetics, The Netherlands Ophthalmic Research Institute (NORI), Amsterdam, The Netherlands.
authors.forename: Theo G M F
authors.initials: TG
authors.lastname: Gorgels
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Hu
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Johan
authors.initials: J
authors.lastname: Toonstra
authors.forename: Paulus T V M
authors.initials: PT
authors.lastname: de Jong
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Christiaan N
authors.initials: CN
authors.lastname: Levelt
authors.forename: Anneke
authors.initials: A
authors.lastname: de Wolf
authors.forename: Willem J P
authors.initials: WJ
authors.lastname: Loves
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Ron
authors.initials: R
authors.lastname: Peek
authors.forename: Arthur A B
authors.initials: AA
authors.lastname: Bergen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D002114:Calcinosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood; D003404:Creatinine / Q000097:blood; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D003404:Creatinine; D027425:ATP-Binding Cassette, Sub-Family C Proteins