title: A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors.
abstract: To identify potential mutations in the gamma-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 gamma-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.
authors.affiliation: Thrombosis and Hemostasis Unit, Institute of Hematology, Rambam Medical Center, and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Brenner
authors.forename: B
authors.initials: B
authors.lastname: Sánchez-Vega
authors.forename: S M
authors.initials: SM
authors.lastname: Wu
authors.forename: N
authors.initials: N
authors.lastname: Lanir
authors.forename: D W
authors.initials: DW
authors.lastname: Stafford
authors.forename: J
authors.initials: J
authors.lastname: Solera
mesh_terms: D000818:Animals; D019735:Carbon-Carbon Ligases / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D020147:Coagulation Protein Disorders / Q000235:genetics*; D004252:DNA Mutational Analysis; D004330:Drosophila / Q000166:cytology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014812:Vitamin K / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D014812:Vitamin K; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase