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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1925-1931. Prepublished online as a Blood First Edition Paper on May 23, 2006; DOI 10.1182/blood-2005-12-010660. This Article Full Text (PDF) Supplemental Table All Versions of this Article: blood-2005-12-010660v1 108/6/1925    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Darghouth, D. Articles by Rosa, J.-P. Search for Related Content PubMed PubMed Citation Articles by Darghouth, D. Articles by Rosa, J.-P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 28, 2005 Accepted April 6, 2006 Compound heterozygosity of novel missense mutations in the -carboxylase gene causes hereditary combined vitamin K-dependent coagulation factor deficiency Dhouha Darghouth, Kevin W Hallgren, Rebecca L Shtofman, Amel Mrad, Youssef Gharbi, Ahmed Maherzi, Radhia Kastally, Sophie LeRicousse, Kathleen Berkner, and Jean-Philippe Rosa* Institut National de la Sante et de la Recherche Medicale; Universite Paris 7, France Lerner Research Institute/Cleveland Clinic Foundation, Cleveland, Ohio, USA Hopital Habib Thameur, Tunis, Tunisia Hopital Mongi Slim, La Marsa, Tunisia Institut National de la Sante et de la Recherche Medicale, France * Corresponding author; email: rosa{at}larib.inserm.fr. Combined vitamin K-dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the - carboxylase which carboxylates VKD proteins to render them active or the vitamin K epoxide reductase (VKORC1) which supplies the reduced vitamin K cofactor required for carboxylation. Such deficiencies are rare, and we report the fourth case resulting from mutations in the carboxylase gene, identified in a Tunisian girl who exhibited impaired function in hemostatic VKD factors that was not restored by vitamin K administration. Sequence analysis of the proposita did not identify any mutations in the VKORC1 gene but, remarkably, revealed three heterozygous mutations in the carboxylase gene that caused the substitutions D31N, W157R and T591K. None of these mutations have previously been reported. Family analysis showed that D31N and T591K were coallelic and maternally transmitted while W157R was transmitted by the father, and a genomic screen of 100 normal individuals ruled out frequent polymorphisms. Mutational analysis indicated wild type activity for the D31N carboxylase. In contrast, the respective W157R and T591K activities were 8% and 0% that of wild type carboxylase, and their compound heterozygosity can therefore account for functional VKD factor deficiency. The implications for carboxylase mechanism are discussed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: -glutamyl carboxylation: squaring the vitamin K cycle Martin J. Shearer Blood 2006 108: 1795-1796. [Full Text] [PDF] This article has been cited by other articles: Q. Li, L. J. Schurgers, A. C.M. Smith, M. Tsokos, J. Uitto, and E. W. Cowen Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency: Compound Heterozygosity for Mutations in the GGCX Gene Am. J. Pathol., February 1, 2009; 174(2): 534 - 540. [Abstract] [Full Text] [PDF] A. Zhu, H. Sun, R. M. Raymond Jr, B. C. Furie, B. Furie, M. Bronstein, R. J. Kaufman, R. Westrick, and D. Ginsburg Fatal hemorrhage in mice lacking {gamma}-glutamyl carboxylase Blood, June 15, 2007; 109(12): 5270 - 5275. [Abstract] [Full Text] [PDF]

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