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

par Munroe, Patricia P.B.;Olgunturk, Rana R.O.;Fryns, Jean-Pierre;Van Maldergem, Lionel;Ziereisen, France ;Yuksel, Bulend;Gardiner, Mark R.M.;Chung, Eddie
Référence Nature genetics, 21, 1, page (142-144)
Publication Publié, 1999-01

Article révisé par les pairs

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Résumé :

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 (refs 2,3). 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 Gia 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 γ- carboxyglutamic acids (Gia) by a specific γ-carboxylase using vitamin K as a cofactor. The modified glutamic acid residues of Gia 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.