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Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16

Item Type:Article
Title:Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16
Creators Name:Fregin, A. and Rost, S. and Wolz, W. and Krebsova, A. and Muller, C.R. and Oldenburg, J.
Abstract: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 {gamma}-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 = 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.
Keywords:Blood Coagulation Factors, Centromere, Chromosome Mapping, DNA Mutational Analysis, Drug Resistance, Genetic Markers, Genotype, Germany, Glutathione Transferase, Hemorrhagic Disorders, Lebanon, Lod Score, Microsatellite Repeats, Mixed Function Oxygenases, Multienzyme Complexes, Pair 16 Human Chromosomes, Pedigree, Recessive Genes, Species Specificity, Vitamin K, Vitamin K 1, Warfarin, Animals, Mice, Rats
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:100
Number:9
Page Range:3229-3232
Date:1 November 2002
Official Publication:https://doi.org/10.1182/blood-2002-03-0698
PubMed:View item in PubMed

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