Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors.
Hereditary combined deficiency of the vitamin K-dependent coagulation factors II, VII, IX, X, protein C, S and protein Z (VKCFD) is a very rare autosomal recessive inherited bleeding disorder. The phenotype may result from functional deficiency of either the gamma-glutamyl carboxylase (GGCX) or the vitamin K epoxide reductase (VKOR) complex. We report on the third case of VKCFD1 with mutations in the gamma-glutamyl carboxylase gene, which is remarkable because of compound heterozygosity. Two mutations were identified: a splice site mutation of exon 3 and a point mutation in exon 11, resulting in the replacement of arginine 485 by proline. Screening of 100 unrelated normal chromosomes by restriction fragment length polymorphism and denaturing high-performance liquid chromatography analysis excluded either mutation as a frequent polymorphism. Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX.
Rost
Simone
S
Institute of Human Genetics, University Würzburg, Würzburg, Germany.
Fregin
Andreas
A
Koch
Dieter
D
Compes
Markus
M
Müller
Clemens R
CR
Oldenburg
Johannes
J
D000595:Amino Acid Sequence; D000818:Animals; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D020147:Coagulation Protein Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D016415:Sequence Alignment; D014812:Vitamin K / Q000502:physiology*
D014812:Vitamin K; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase