Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia 1. 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 2, 3, 4. 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 5. It is a member of the Gla protein family, which includes osteocalcin 6, another skeletal ECM protein, and a number of coagulation factors 7 (factors II, VII, IX, X and proteins S and C). All members of this family have glutamic acid residues modified to γ-carboxyglutamic acids (Gla) by a specific γ-carboxylase using vitamin K as a cofactor 8, 9. 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 10. Mglap-deficient mice (Mglap–/–) have been reported to have inappropriate calcification of cartilage 4. 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.