title: Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI.
abstract: The mineralisation disorder pseudoxanthoma elasticum (PXE) is associated with mutations in the transporter protein ABCC6. Patients with PXE suffer from calcified lesions in the skin, eyes and vasculature, and PXE is related to a more severe vascular calcification syndrome called generalised arterial calcification of infancy (GACI). Mutations in ABCC6 are linked to reduced levels of circulating vitamin K. Here, we describe a mutation in the zebrafish (Danio rerio) orthologue abcc6a, which results in extensive hypermineralisation of the axial skeleton. Administration of vitamin K to embryos was sufficient to restore normal levels of mineralisation. Vitamin K also reduced ectopic mineralisation in a zebrafish model of GACI, and warfarin exacerbated the mineralisation phenotype in both mutant lines. These data suggest that vitamin K could be a beneficial treatment for human patients with PXE or GACI. Additionally, we found that abcc6a is strongly expressed at the site of mineralisation rather than the liver, as it is in mammals, which has significant implications for our understanding of the function of ABCC6.
authors.affiliation: Hubrecht Institute - KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.
authors.forename: Eirinn W
authors.initials: EW
authors.lastname: Mackay
authors.affiliation: Hubrecht Institute - KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Apschner
authors.affiliation: Hubrecht Institute - KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands EZO, WUR, Wageningen 6709 PG, The Netherlands Institute of Cardiovascular Organogenesis and Regeneration, University of Münster, Münster 48149, Germany Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Münster 48149, Germany schultes@ukmuenster.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D017931:DNA Primers / Q000235:genetics; D017403:In Situ Hybridization; D009154:Mutation / Q000235:genetics; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D061205:Vascular Calcification / Q000235:genetics* / Q000378:metabolism; D014812:Vitamin K / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C553407:ABCC6A protein, zebrafish; D018528:ATP-Binding Cassette Transporters; D000880:Anthraquinones; D017931:DNA Primers; D029961:Zebrafish Proteins; D014812:Vitamin K; D014859:Warfarin; C010078:alizarin
keywords: ABCC6; Mineralisation; PXE; Vitamin K; Zebrafish