title: Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues.
abstract: 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.
authors.affiliation: Department of Dermatology, Jefferson Medical College, 233 S. 10th Street, Suite 322 BLSB, Philadelphia, PA 19107, USA. John.Klement@jefferson.edu
authors.forename: John F
authors.initials: JF
authors.lastname: Klement
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Qiu-Jie
authors.initials: QJ
authors.lastname: Jiang
authors.forename: Joseph
authors.initials: J
authors.lastname: Terlizzi
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Choi
authors.forename: Norihiro
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Kehua
authors.initials: K
authors.lastname: Li
authors.forename: Leena
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D015415:Biomarkers; D002114:Calcinosis / Q000209:etiology / Q000473:pathology*; D003238:Connective Tissue / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D024022:Fibrillar Collagens / Q000648:ultrastructure; D020868:Gene Silencing; D018390:Gene Targeting; D051379:Mice; D008822:Mice, Transgenic; D008903:Minerals / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011561:Pseudoxanthoma Elasticum / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D012867:Skin / Q000000981:diagnostic imaging / Q000473:pathology; D014057:Tomography, X-Ray Computed; D014738:Vibrissae / Q000473:pathology / Q000648:ultrastructure
chemical_list: D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D024022:Fibrillar Collagens; D008903:Minerals; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse