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Molecular and Cellular Biology, September 2005, p. 8299-8310, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8299-8310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

John F. Klement,1,{dagger}* Yasushi Matsuzaki,1,{dagger} Qiu-Jie Jiang,1 Joseph Terlizzi,1 Hae Young Choi,1 Norihiro Fujimoto,1 Kehua Li,1 Leena Pulkkinen,1 David E. Birk,2 John P. Sundberg,4 and Jouni Uitto1,3

Departments of Dermatology and Cutaneous Biology,1 Pathology, Anatomy, and Cell Biology,2 Biochemistry and Molecular Pharmacology, Jefferson Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania,3 The Jackson Laboratory, Bar Harbor, Maine4

Received 30 March 2005/ Returned for modification 1 June 2005/ Accepted 17 June 2005

Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6–/– mice but was not observed in Abcc6+/– or Abcc6+/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6–/– mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease.

* Corresponding author. Mailing address: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 233 S. 10th Street, Suite 322 BLSB, Philadelphia, PA 19107. Phone: (215) 503-4488. Fax: (215) 503-5788. E-mail: John.Klement{at}jefferson.edu.

{dagger} J.F.K. and Y.M. contributed equally to this study.

Molecular and Cellular Biology, September 2005, p. 8299-8310, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8299-8310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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