Circulating matrix γ‐carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome

Background and objectives: Matrix γ‐carboxyglutamate protein (MGP), a vitamin K‐dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportuni...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2011-06, Vol.9 (6), p.1225-1235
Main Authors: CRANENBURG, E. C. M., VAN SPAENDONCK‐ZWARTS, K. Y., BONAFE, L., MITTAZ CRETTOL, L., RÖDIGER, L. A., DIKKERS, F. G., VAN ESSEN, A. J., SUPERTI‐FURGA, A., ALEXANDRAKIS, E., VERMEER, C., SCHURGERS, L. J., LAVERMAN, G. D.
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - drug therapy
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
arterial calcification
Arteries
Calcinosis - drug therapy
Calcinosis - genetics
Calcinosis - pathology
Calcium-Binding Proteins - blood
Calcium-Binding Proteins - drug effects
Calcium-Binding Proteins - genetics
Cartilage Diseases - drug therapy
Cartilage Diseases - genetics
Cartilage Diseases - pathology
Extracellular Matrix Proteins - blood
Extracellular Matrix Proteins - drug effects
Extracellular Matrix Proteins - genetics
Hand Deformities, Congenital - drug therapy
Hand Deformities, Congenital - genetics
Hand Deformities, Congenital - pathology
Homozygote
Humans
Keutel syndrome
Matrix Gla Protein
Mutation
osteopontin
Pulmonary Valve Stenosis - drug therapy
Pulmonary Valve Stenosis - genetics
Pulmonary Valve Stenosis - pathology
Vitamin K - therapeutic use
vitamin K
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Summary:Background and objectives: Matrix γ‐carboxyglutamate protein (MGP), a vitamin K‐dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. Methods: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. Results: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated MGP levels. Phosphorylated MGP was also found to be present in the first KS patient originally described. Conclusions: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP‐deficient mice and humans.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2011.04263.x