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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4554-4559
RAPID COMMUNICATION
A Missense Mutation in  -Glutamyl Carboxylase Gene Causes Combined
Deficiency of All Vitamin K-Dependent Blood Coagulation Factors
Benjamin Brenner,
Beatriz Sánchez-Vega,
Sheue-Mei Wu,
Naomi Lanir,
Darrel W. Stafford, and
Jesus Solera
From the Thrombosis and Hemostasis Unit, Institute of Hematology,
Rambam Medical Center, and Bruce Rappaport Faculty of Medicine,
Technion, Haifa, Israel; the Unit of Molecular Genetics, S
Biochemistry, Hospital La Paz, Madrid, Spain; and the Department of
Biology, University of North Carolina-Chapel Hill, Chapel Hill, NC.
To identify potential mutations in the  -glutamyl carboxylase
gene, the sequence of all exons and intron/exon borders was determined
in 4 patients from a consanguineous kindred with combined deficiency of
all vitamin K-dependent procoagulants and anticoagulants and
results were compared with normal genomic sequence. All 4 patients were
homozygous for a point mutation in exon 9 that resulted in the
conversion of an arginine codon (CTG) to leucine codon (CGG) at residue
394. Screening of this mutation based on introduction of Alu I
site in amplified fragment from normal allele but not from the mutated
allele showed that 13 asymptomatic members of the kindred were
heterozygous for the mutation. The mutation was not found in 340 unrelated normal chromosomes. The segregation pattern of the mutation
which is the first reported in the -glutamyl carboxylase gene fits
perfectly with phenotype of the disorder and confirms the suggested
autosomal recessive pattern of inheritance of combined deficiency of
all vitamin K-dependent procoagulants and anticoagulants in
this kindred. The mutated carboxylase protein expressed in Drosophila
cells was stable but demonstrated threefold reduced activity compared
with WT carboxylase, confirming that the L394R mutation results in a
defective carboxylase.
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