Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome

Abstract

Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia. A genome search using homozygosity mapping provided evidence of linkage to chromosome 12p12.3-13.1 (maximum multipoint lod score, 4.06). MGP was a candidate on the basis of its localization to this chromosomal region and the known function of its protein. MGP maps to chromosome 12p near D12S363. Human MGP is a 10-kD skeletal extracellular matrix (ECM) protein that consists of an 84-aa mature protein and a 19-aa transmembrane signal peptide. It is a member of the Gla protein family, which includes osteocalcin, another skeletal ECM protein, and a number of coagulation factors (factors II, VII, IX, X and proteins S and C). All members of this family have glutamic acid residues modified to gamma-carboxyglutamic acids (Gla) by a specific gamma-carboxylase using vitamin K as a cofactor. The modified glutamic acid residues of Gla proteins confer a high affinity for mineral ions such as calcium, phosphate and hydroxyapatite crystals, the mineral components of the skeletal ECM. The pattern and tissue distribution of Mgp expression in mice suggest a role for Mgp in regulating ECM calcification. Mglap-deficient mice (Mglap-/-) have been reported to have inappropriate calcification of cartilage. Mutational analysis of MGP in three unrelated probands identified three different mutations: c.69delG, IVS1-2A-->G and c.113T-->A. All three mutations predict a non-functional MGP. Our data indicate that mutations in MGP are responsible for KS and confirm its role in the regulation of extracellular matrix calcification.

Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells

“…Together, our results suggest that MGP affects several of the TGF-␤ growth factors, thereby having the ability to alter the overall response to TGF-␤ growth factors. This concept would be consistent with the wide range of vascular and non-vascular abnormalities seen in MGP deficiency (3)(4)(5)(6)(7)(8), and may also be consistent with a role for combined TGF-␤/BMP regulation in SMC differentiation. The Krü ppel-like transcription factor 4 (KLF4/GKLF) has been identified as a target of both BMP and TGF-␤1 in regulation of vascular SMC phenotype (41), and may be an important mediator.…”

“…Several features in MGP deficiency (3)(4)(5)(6)(7)(8) suggest involvement of vascular endothelium, including peripheral pulmonary stenosis, that may result from a failure in angiogenesis or vessel fusion (9, 10), arterial calcification that may relate to endothelial dysfunction during vascular maturation (11), and loss of architecture and hypertrophic chondrocytes in the bone growth plate that may relate to disturbed vascularization (12). Increased MGP expression has been reported in tube-forming EC as determined by subtractive hybridization (13), and in myometrial EC treated with VEGFs as determined by microarray analysis (14).…”

Low vitamin K status is associated with osteoarthritis in the hand and knee

“…First, inadequate ␥-carboxylation of Gas-6, as may occur with insufficient vitamin K, impairs the function of Gas-6 (2,18,19) and, as such, may impair chondrocyte viability in articular cartilage. Second, both mice and humans deficient in MGP express phenotypes that are similar to that seen with warfarin embryopathy, with growth plate calcification abnormalities that in theory might be mimicked by the process of osteophyte formation (11,13). Further, MGP is an important inhibitor of chondrogenesis via binding to bone morphogenetic protein 2 (39,40) and of extracellular matrix calcification via circulating complexes of fetuin and mineral (41).…”

“…Vitamin K also regulates growth plate cartilage calcification, as revealed by effects of vitamin K antagonism by warfarin (6)(7)(8)(9)(10). Genetic deficiencies of MGP in humans and mice have been linked to skeletal abnormalities, including premature epiphyseal calcification and shortening of long limb bones, reflecting endochondral bone formation (11)(12)(13)(14).…”

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

“…36 Mutations in MGP cause Keutel syndrome, which features chondrodysplasia punctata, midfacial hypoplasia, peripheral pulmonary stenosis and progressive soft tissue, and vascular calcifications. 37,38 We speculate that ARSE might undergo γ-carboxylation and have functions similar to matrix Gla protein and osteocalcin, by catalyzing the desulfation of a critical growth plate component that inhibits calcification. Alternatively, ARSE may require vitamin K for normal growth plate mineralization in a pathway independent of γ-carboxylation.…”