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Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

Olivier Vanakker UGent, Ludovic Martin, Leon J Schurgers, Daniela Quaglino, Laura Costrop, Cees Vermeer, Ivonne Pasquali-Ronchetti, Paul Coucke UGent and Anne De Paepe UGent (2010) LABORATORY INVESTIGATION. 90(6). p.895-905
abstract
Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE. Laboratory Investigation (2010) 90, 895-905; doi:10.1038/labinvest.2010.68; published online 5 April 2010
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
UP-REGULATION, ABCC6 MUTATIONS, MUSCLE-CELL CALCIFICATION, BONE MORPHOGENETIC PROTEIN-2, PSEUDOXANTHOMA ELASTICUM PATIENTS, MATRIX GLA PROTEIN, vitamin K-dependent proteins, vitamin K, elastic fibers, fetuin-A, pseudoxanthoma elasticum, mineralization, GENE, DEFICIENCY, FETUIN-A, DISEASE
journal title
LABORATORY INVESTIGATION
Lab. Invest.
volume
90
issue
6
pages
895 - 905
Web of Science type
Article
Web of Science id
000278091300008
JCR category
PATHOLOGY
JCR impact factor
4.405 (2010)
JCR rank
9/75 (2010)
JCR quartile
1 (2010)
ISSN
0023-6837
DOI
10.1038/labinvest.2010.68
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1013912
handle
http://hdl.handle.net/1854/LU-1013912
date created
2010-07-22 15:10:25
date last changed
2016-12-19 15:42:12
@article{1013912,
  abstract     = {Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE. Laboratory Investigation (2010) 90, 895-905; doi:10.1038/labinvest.2010.68; published online 5 April 2010},
  author       = {Vanakker, Olivier and Martin, Ludovic and Schurgers, Leon J and Quaglino, Daniela and Costrop, Laura and Vermeer, Cees and Pasquali-Ronchetti, Ivonne and Coucke, Paul and De Paepe, Anne},
  issn         = {0023-6837},
  journal      = {LABORATORY INVESTIGATION},
  keyword      = {UP-REGULATION,ABCC6 MUTATIONS,MUSCLE-CELL CALCIFICATION,BONE MORPHOGENETIC PROTEIN-2,PSEUDOXANTHOMA ELASTICUM PATIENTS,MATRIX GLA PROTEIN,vitamin K-dependent proteins,vitamin K,elastic fibers,fetuin-A,pseudoxanthoma elasticum,mineralization,GENE,DEFICIENCY,FETUIN-A,DISEASE},
  language     = {eng},
  number       = {6},
  pages        = {895--905},
  title        = {Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome},
  url          = {http://dx.doi.org/10.1038/labinvest.2010.68},
  volume       = {90},
  year         = {2010},
}

Chicago
Vanakker, Olivier, Ludovic Martin, Leon J Schurgers, Daniela Quaglino, Laura Costrop, Cees Vermeer, Ivonne Pasquali-Ronchetti, Paul Coucke, and Anne De Paepe. 2010. “Low Serum Vitamin K in PXE Results in Defective Carboxylation of Mineralization Inhibitors Similar to the GGCX Mutations in the PXE-like Syndrome.” Laboratory Investigation 90 (6): 895–905.
APA
Vanakker, O., Martin, L., Schurgers, L. J., Quaglino, D., Costrop, L., Vermeer, C., Pasquali-Ronchetti, I., et al. (2010). Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome. LABORATORY INVESTIGATION, 90(6), 895–905.
Vancouver
1.
Vanakker O, Martin L, Schurgers LJ, Quaglino D, Costrop L, Vermeer C, et al. Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome. LABORATORY INVESTIGATION. 2010;90(6):895–905.
MLA
Vanakker, Olivier, Ludovic Martin, Leon J Schurgers, et al. “Low Serum Vitamin K in PXE Results in Defective Carboxylation of Mineralization Inhibitors Similar to the GGCX Mutations in the PXE-like Syndrome.” LABORATORY INVESTIGATION 90.6 (2010): 895–905. Print.