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Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1763-1773; doi:10.1093/hmg/ddi183
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

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

Theo G.M.F. Gorgels1, Xiaofeng Hu1, George L. Scheffer3, Allard C. van der Wal4, Johan Toonstra5, Paulus T.V.M. de Jong1,6,8, Toin H. van Kuppevelt9, Christiaan N. Levelt2, Anneke de Wolf1, Willem J.P. Loves1, Rik J. Scheper3, Ron Peek1 and Arthur A.B. Bergen1,7,*

1Department of Molecular and Clinical Ophthalmogenetics and 2Department Molecular Visual Plasticity, The Netherlands Ophthalmic Research Institute (NORI), Amsterdam, The Netherlands, 3Department of Pathology, Free University Amsterdam, 4Department of Cardiovascular Pathology, AMC, Amsterdam, 5Department of Dermatology, UMC, Utrecht, The Netherlands, 6Department of Ophthalmology and 7Department of Clinical Genetics, AMC, Amsterdam, The Netherlands, 8Department of Epidemiology and Biostatistics, EMC, Rotterdam, The Netherlands and 9Department of Biochemistry, NCMLS, Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands

* To whom correspondence should be addressed at: Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Ophthalmic Research Institute, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. Tel: +31 205666101; Fax: +31 205666121; Email: a.bergen{at}ioi.knaw.nl

Received March 24, 2005; Accepted May 3, 2005

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.


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