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

Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder charact erized by abnormal cartilage calcification, peripheral pulmonary stenosis a nd midfacial hypoplasia(1). A genome search using homozygosity mapping prov ided 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(2-4). MGP maps to chromosome 12p near D12S363 (refs 2,3). Human MCP is a 10-kD skeletal extr acellular 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 an d C). All members of this family have glutamic acid residues modified to ga mma-carboxyglutamic acids (Gla) by a specific gamma-carboxylase using Vitam in K as a cofactors(8,9). The modified glutamic acid residues of Gla protei ns confer a high affinity for mineral ions such as calcium, phosphate and h ydroxyapatite crystals, the mineral components of the skeletal ECM. The pat tern and tissue distribution of Mgp expression in mice suggest a role for M gp in regulating ECM calcification(10). Mglap-deficient mice (Mglap(-/-)) h ave been reported to have inappropriate calcification of cartilage(4). Muta tional analysis of MGP in three unrelated probands identified three differe nt mutations: c.69delG, IVS1-2A-->G and c.113T-->A. All three mutations pre dict a non-functional MGP. Our data indicate that mutations in MGP are resp onsible for KS and confirm its role in the regulation of extracellular matr ix calcification.