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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-03-0698.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3229-3232
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Homozygosity mapping of a second gene locus for hereditary
combined deficiency of vitamin K-dependent clotting factors to the
centromeric region of chromosome 16
Andreas Fregin,
Simone Rost,
Werner Wolz,
Alice Krebsova,
Clemens R. Muller, and
Johannes Oldenburg
From the Institut für Humangenetik
Universität Würzburg Biozentrum, Würzburg, Germany;
the Gene Mapping Centre, Max Delbrück Center for Molecular
Medicine, Berlin, Germany; the Institut für Experimentelle
Hämatologie und Transfusionsmedizin, Bonn, Germany; and the
Institute of Transfusion Medicine and Immune Haematology of the DRK
Blood Donor Service, Frankfurt, Germany.
Familial multiple coagulation factor deficiency (FMFD) of
factors II, VII, IX, X, protein C, and protein S is a very rare bleeding disorder with autosomal recessive inheritance. The phenotypic presentation is variable with respect to the residual activities of the
affected proteins, its response to oral administration of vitamin K,
and to the involvement of skeletal abnormalities. The disease may
result either from a defective resorption/transport of vitamin K to the
liver, or from a mutation in one of the genes encoding  -carboxylase
or other proteins of the vitamin K cycle. We have recently presented
clinical details of a Lebanese family and a German family with 10 and 4 individuals, respectively, where we proposed autosomal recessive
inheritance of the FMFD phenotype. Biochemical investigations of
vitamin K components in patients' serum showed a significantly
increased level of vitamin K epoxide, thus suggesting a defect in one
of the subunits of the vitamin K 2,3-epoxide reductase (VKOR) complex.
We now have performed a genome-wide linkage analysis and found
significant linkage of FMFD to chromosome 16. A total maximum 2-point
LOD score of 3.4 at  = 0 was obtained in the interval between
markers D16S3131 on 16p12 and D16S419 on 16q21. In both families,
patients were autozygous for 26 and 28 markers, respectively, in an
interval of 3 centimorgans (cM). Assuming that FMFD and warfarin
resistance are allelic, conserved synteny between human and mouse
linkage groups would restrict the candidate gene interval to the
centromeric region of the short arm of chromosome 16.
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