title: Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery?
abstract: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by a progressive mineralization of connective tissue, resulting in skin, arterial and eye disease. Classical PXE is caused by mutations in the ABCC6 gene, which encodes a member of the ABCC (MRP) family of organic anion transporters. Recent studies on Abcc6(-/-) mice show that the absence of ABCC6 in the liver is crucial for PXE and confirm the "metabolic disease hypothesis" for PXE, which states that tissue calcification is due to the absence of a plasma factor secreted from the basolateral hepatocyte membrane. We propose that this plasma factor is vitamin K (precursor). We propose that vitamin K (precursor) is secreted by ABCC6 from the liver as a glutathione--(or glucuronide)--conjugate and that this supplements the vitamin K need of peripheral tissues that receive insufficient vitamin from the diet, because dietary vitamin K is effectively extracted from blood by the liver. Peripheral tissue vitamin K is needed for the gamma-carboxylation of glutamate residues in proteins known to be required for counteracting calcification of connective tissue throughout the body. Our hypothesis explains the known facts of PXE and also explains why PXE-like symptoms can occur in patients with mutations in the gamma-glutamyl carboxylase gene (encoding the enzyme responsible for protein carboxylase) and in rats treated with vitamin K antagonists. The hypothesis implies that the symptoms of PXE can be prevented or mitigated by providing patients (intravenously) with a form of plasma vitamin K (precursor) that can be used by peripheral tissues.
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands. p.borst@nki.nl
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
authors.forename: Reinier
authors.initials: R
authors.lastname: Schlingemann
mesh_terms: D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011561:Pseudoxanthoma Elasticum / Q000378:metabolism*; D014812:Vitamin K / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014812:Vitamin K; C102029:ABCC6 protein, human