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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi183
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 24, 2005
Revised May 3, 2005
Accepted May 3, 2005

Article

Disruption of Abcc6 in the mouse: Novel insight in the pathogenesis of pseudoxanthoma elasticum

Theo G.M.F. Gorgels 1, Xiaofeng Hu 1, George L. Scheffer 2, Allard C. Van der Wal 3, Johan Toonstra 4, Paulus T.V.M. de Jong 5, Toin H. Van Kuppevelt 6, Christiaan N. Levelt 7, Anneke de Wolf 1, Willem J.P. Loves 1, Rik J. Schepers 2, Ron Peek 1, and Arthur A.B. Bergen 8*

1 Dept. of Molecular and Clinical Ophthalmogenetics, The Netherlands Ophthalmic Research Institute (NORI), Amsterdam, NL
2 Dept. of Pathology, Free University Amsterdam
3 Dept. of Cardiovascular Pathology, AMC
4 Dept. of Dermatology, UMC, Utrecht, NL
5 Dept. of Molecular and Clinical Ophthalmogenetics, The Netherlands Ophthalmic Research Institute (NORI), Amsterdam, NL; Dept. of Ophthalmology, AMC, Amsterdam, NL; Dept. of Epidemiology and Biostatistics, EMC, Rotterdam, NL
6 Dept. of Biochemistry, NCMLS, Medical Center, Radboud University Nijmegen, Nijmegen, NL
7 Dept. Molecular Visual Plasticity, NORI, Amsterdam, NL
8 Dept. of Clinical and Molecular Ophthalmogenetics, The Netherlands Ophthalmic Research Institute, Amsterdam, NL, Meibergdreef 47, 1105 BA Amsterdam; Dept. of Clinical Genetics, AMC, Amsterdam, NL

* To whom correspondence should be addressed.
Arthur A.B. Bergen, E-mail: A.bergen{at}ioi.knaw.nl


  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 occurred in old mice 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.


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