title: Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.
abstract: OBJECTIVE
  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.
authors: VitaK and Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: E C M
authors: EC
authors: Cranenburg
authors: K Y
authors: KY
authors: VAN Spaendonck-Zwarts
authors: L
authors: L
authors: Bonafe
authors: L
authors: L
authors: Mittaz Crettol
authors: L A
authors: LA
authors: Rödiger
authors: F G
authors: FG
authors: Dikkers
authors: A J
authors: AJ
authors: VAN Essen
authors: A
authors: A
authors: Superti-Furga
authors: E
authors: E
authors: Alexandrakis
authors: C
authors: C
authors: Vermeer
authors: L J
authors: LJ
authors: Schurgers
authors: G D
authors: GD
authors: Laverman
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001158:Arteries; D002114:Calcinosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000097:blood / Q000187:drug effects* / Q000235:genetics*; D002357:Cartilage Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000097:blood / Q000187:drug effects* / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D006801:Humans; D009154:Mutation; D011666:Pulmonary Valve Stenosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014812:Vitamin K / Q000627:therapeutic use*; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D014812:Vitamin K; D000097568:Matrix Gla Protein