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

Abstract

Summary. Background and objectives: Matrix c-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.

Characterization of vitamin K–dependent carboxylase mutations that cause bleeding and nonbleeding disorders

“…In addition, it has been shown that supplementation of high-dose vitamin K did not increase the level of cMGP in patients with Keutel syndrome. 51 Therefore, the improvement of MGP carboxylation by menaquinones may account for extrahepatic cell utilization of these K vitamins 52 for wild-type GGCX carboxylation. When the defects are caused by mutations in GGCX or MGP, menaquinones cannot ameliorate the carboxylation of MGP.…”

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

“…43 Similarly, cranial CT scan and multislice CT scanning of the coronary arteries revealed no calcification in a 21-year-old men with genetically confirmed Keutel syndrome. 44 Unfortunately, their PWVs were not reported. One hypothesis that could be in line with our results and the absence of calcifications in tomography in Keutel patients is that a high level of inactive MGP leads to an increase in the number, or in the size, of calcifications, but sufficiently scattered in the vessels not to be detectable by tomography.…”

A Novel MGP Gene Mutation Causing Keutel Syndrome in a Brazilian Patient

“…However, literature review revealed only 10 patients with molecular diagnosis [Munroe et al, 1999;Hur et al, 2005;Cranenburg et al, 2011;Weaver et al, 2014;Tüysüz et al, 2015;Bayramoğlu et al, 2016]. These patients shared 7 distinct pathogenic variants: 3 were donator or acceptor splice site type (IVS1-2A>G/c.62-2A>G; IVS2+1G>A; IVS1+1G>A/c.61+1G>A), 3 were deletion variants [1 missense (c.113T>A), 1 nonsense (c.79G>T; p.Glu27X), and 1 frameshift (c.69delG)], and 1 was a partial deletion of exon 4.…”