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

Nature Genetics volume 21, pages 142–144 (1999)Cite this article

Abstract

Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia1. 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 protein2,3,4. 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 peptide5. It is a member of the Gla protein family, which includes osteocalcin6, another skeletal ECM protein, and a number of coagulation factors7 (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 cofactor8,9. 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 calcification10. Mglap -deficient mice ( Mglap–/–) have been reported to have inappropriate calcification of cartilage4. 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.

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Figure 1: X-rays of auricles and chest of family KS1 proband and a normal control.
Figure 2: Pedigrees, chromosome 12 haplotypes and MGP mutations in KS families.

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References

  1. Keutel, J., Jorgensen, G. & Gabriel, P. A new autosomal recessive syndrome peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcifications-ossification. Birth Defects Orig. Artic Ser. VIII 5, 60–68 (1972 ).

    Google Scholar 

  2. Johnson, T.L., Sakaguchi, A.Y., Lalley, P.A. & Leach, R.J. Chromosomal assignment in mouse of matrix GLA protein and bone GLA protein genes. Genomics 11, 770– 772 (1991).

    Article  CAS  Google Scholar 

  3. Watanabe, I., Tsukamoto, K., Shiba, T. & Emi, M. Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human matrix Gla protein (MGP) locus. J. Hum. Genet. 43, 75–76 (1998).

    Article  CAS  Google Scholar 

  4. Luo, G. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386, 78– 81 (1997).

    Article  CAS  Google Scholar 

  5. Hale, J.E., Fraser, J.D. & Price, P.A. The identification of matrix Gla protein in cartilage. J. Biol. Chem. 263, 5820– 5824 (1988).

    CAS  PubMed  Google Scholar 

  6. Ducy, P. et al. Increased bone formation in osteocalcin-deficient mice. Nature 382, 448–452 ( 1996).

    Article  CAS  Google Scholar 

  7. Furie, B. & Furie B.C. The molecular basis of blood coagulation. Cell 53, 505–518 (1988).

    Article  CAS  Google Scholar 

  8. Gallop, P.M., Lian, J.B. & Hauschka, P.V. Carboxylated calcium-binding proteins and vitamin K. N. Engl. J. Med. 302, 1460– 1466 (1980).

    Article  CAS  Google Scholar 

  9. Dowd, P., Hershline, R., Ham, S.W. & Naganathan, S. Vitamin K and energy transduction: a base strength amplification mechanism. Science 269, 1684–1691 ( 1995).

    Article  CAS  Google Scholar 

  10. Luo, G., D'Souza, R. & Karsenty, G. The matrix gla protein gene product is a marker of the chondrogenesis cell lineage during mouse development. J. Bone Miner. Res. 10, 325–334 ( 1995).

    Article  CAS  Google Scholar 

  11. Say, B., Balci, S., Pinar, T., Israel, R. & Atasu, M. Unusual calcium deposition in cartilage associated with short stature and peculiar facial features: a case report. Pediatr. Radiol. 1, 127–129 ( 1973).

    Article  CAS  Google Scholar 

  12. Cormode, E.J., Dawson, M. & Lowry, R.B. Keutel syndrome: clinical report and literature review. Am. J. Med. Genet. 24, 289– 294 (1986).

    Article  CAS  Google Scholar 

  13. Fryns, J.P., van Fleteren, A., Mattelaer, P. & van den Berghe, H. Calcification of cartilages, brachytelephalangy and peripheral pulmonary stenosis: confirmation of the Keutel syndrome. Eur. J. Pediatr. 142, 201–203 (1984).

    Article  CAS  Google Scholar 

  14. Khosroshahi, H.E., Uluoglu, O., Olgunturk, R. & Basaklar, C. Keutel syndrome: a report of four cases. Eur. J. Pediatr. 149, 188–191 (1989).

    Article  CAS  Google Scholar 

  15. Cancela, L., Hsieh, C.L., Francke, U. & Price, P.A. Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene. J. Biol. Chem. 265, 15040– 15048 (1990).

    CAS  PubMed  Google Scholar 

  16. Fraser, J.D. & Price, P.A. Lung, heart, & kidney express high levels of mRNA for the vitamin K-dependent matrix gla protein. J. Biol. Chem. 263, 11033–11036 (1988).

    CAS  PubMed  Google Scholar 

  17. Howe, A.M. et al. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Am. J. Med. Genet. 58, 238–244 (1995).

    Article  CAS  Google Scholar 

  18. Pettifor, J.M. & Benson, R. Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J. Pediatr. 86, 459–462 (1975).

    Article  CAS  Google Scholar 

  19. Pauli, R.M., Lian, J.B., Mosher, D.F. & Suttie, J.W. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am. J. Hum. Genet. 41, 566–583 (1990).

    Google Scholar 

  20. Spranger, J.W., Opitz, J.M. & Bidder, U. Heterogeneity of chondrodysplaisa punctata. Hum. Genet. 11, 190–212 (1970).

    Article  Google Scholar 

  21. Sheffield, L.J., Danks, D.M., Mayne, V. & Hutchinson, L.A. Chondrodysplasia punctata—23 cases of a mild and relatively common variety. J. Pediatr. 89, 916–923 (1976).

    Article  CAS  Google Scholar 

  22. Fasco, M.J., Hildebrandt, E.F. & Suttie, J.W. Evidence that warfarin anticoagulant action involves two distinct reductase activities. J. Biol. Chem. 257 , 11210–11212 (1982).

    CAS  PubMed  Google Scholar 

  23. Franco, B. et al. A cluster of sulfatase genes on Xp22.3 mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 81, 1–20 (1995 ).

    Article  Google Scholar 

  24. Kruglyak, A.F., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis a unified multipoint approach. Am. J. Hum. Genet. 58, 1347– 1363 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Collins, A., Frezal, J., Teague J. & Morton, N.E. A metric map of humans: 23,500 loci in 850 bands. Proc. Natl Acad. Sci. USA 93, 14771–14775 ( 1996).

    Article  CAS  Google Scholar 

  26. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  Google Scholar 

  27. Munroe, P.B. et al. Spectrum of mutations in the Batten disease gene, CLN3. Am. J. Hum. Genet. 61, 310–316 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the families for their participation in this study and S. Strautnieks, M. Williamson and N. Parkinson for excellent technical assistance.

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Authors and Affiliations

  1. Department of Paediatrics, Royal Free and University College Medical School, The Rayne Institute, University Street , London, UK

    Patricia B. Munroe, R. Mark Gardiner & Eddie Chung

  2. Department of Paediatric Cardiology, Gazi University Hospitals, Ankara, Turkey

    Rana O. Olgunturk

  3. Centre for Human Genetics, University of Leuven, Leuven, Belgium

    Jean-Pierre Fryns

  4. Centre for Human Genetics, Institut de Pathologie et de Génétique, Loverval, Belgium

    Lionel Van Maldergem

  5. Department of Radiology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium

    France Ziereisen

  6. Department of Paediatrics, Chase Farm Hospitals NHS Trust, London, UK

    Bulend Yuksel

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  1. Patricia B. Munroe
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Correspondence to Patricia B. Munroe.

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Munroe, P., Olgunturk, R., Fryns, JP. et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21, 142–144 (1999). https://doi.org/10.1038/5102

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