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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-03-0698.
Submitted March 7, 2002
Accepted May 12, 2002
Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors (FMFD) to the centromeric region of chromosome 16
Andreas Fregin, Simone Rost, Werner Wolz, Alice Krebsova, Clemens R Muller, and Johannes Oldenburg*
Molecular Haemostasis, Institute of Human Genetics, Wuerzburg, Germany
Gene Mapping Centre, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
Molecular Haemostasis, Institute of Human Genetics, Wuerzburg, Germany; Molecular Haemostasis, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany; Molecular Haemostasis, Institute of Transfusion Medicine and Immune Haematology, DRK Blood Donor Service Hessen, Frankfurt, Germany
* Corresponding author; email: joldenburg{at}bsdhessen.de.
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 and a German family with ten and four 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-epoxidase reductase (VKOR) complex. We now have performed a genome wide linkage analysis and found significant linkage of FMFD to chromosome 16. A total maximum two-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 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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