Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16.
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 theta = 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.
Fregin
Andreas
A
Institut für Humangenetik Universität Würzburg Biozentrum, Würzburg, Germany.
Rost
Simone
S
Wolz
Werner
W
Krebsova
Alice
A
Muller
Clemens R
CR
Oldenburg
Johannes
J
D000818:Animals; D001779:Blood Coagulation Factors / Q000032:analysis*; D002503:Centromere / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D005838:Genotype; D005858:Germany; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics; D006474:Hemorrhagic Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007861:Lebanon; D008126:Lod Score; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics*; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics; D010375:Pedigree; D051381:Rats; D013045:Species Specificity; D014812:Vitamin K / Q000502:physiology* / Q000627:therapeutic use; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000097:blood; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology
D001779:Blood Coagulation Factors; D005819:Genetic Markers; D009097:Multienzyme Complexes; D014812:Vitamin K; C016186:vitamin K1 oxide; D014859:Warfarin; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D005982:Glutathione Transferase