Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K–dependent coagulation factor deficiency
| Autor: | Dhouha Darghouth, Kevin W. Hallgren, Sophie Lericousse, Jean Rosa, Kathleen L. Berkner, Youssef Gharbi, Radhia Kastally, Amel Mrad, Rebecca L. Shtofman, Ahmed Maherzi |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Heterozygote Vitamin K Coagulation Factor Deficiency VKORC1 Gene DNA Mutational Analysis Molecular Sequence Data Immunology Mutation Missense Coagulation Protein Disorders Biology Compound heterozygosity medicine.disease_cause Polymerase Chain Reaction Hemostasis Thrombosis and Vascular Biology Biochemistry Gamma-glutamyl carboxylase Mixed Function Oxygenases Evolution Molecular Blood Coagulation Disorders Inherited Vitamin K Epoxide Reductases medicine Humans Amino Acid Sequence Child Alleles Conserved Sequence DNA Primers Genetics Mutation Base Sequence Sequence Homology Amino Acid Infant Cell Biology Hematology Molecular biology Pedigree Pyruvate carboxylase Amino Acid Substitution Carbon-Carbon Ligases Female Vitamin K epoxide reductase VKORC1 |
| Zdroj: | Blood. 108:1925-1931 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2005-12-010660 |
| Popis: | Hereditary combined vitamin K–dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the γ-carboxylase, which carboxylates VKD proteins to render them active, or the vitamin K epoxide reductase (VKORC1), which supplies the reduced vitamin K cofactor required for carboxylation. Such deficiencies are rare, and we report the fourth case resulting from mutations in the carboxylase gene, identified in a Tunisian girl who exhibited impaired function in hemostatic VKD factors that was not restored by vitamin K administration. Sequence analysis of the proposita did not identify any mutations in the VKORC1 gene but, remarkably, revealed 3 heterozygous mutations in the carboxylase gene that caused the substitutions Asp31Asn, Trp157Arg, and Thr591Lys. None of these mutations have previously been reported. Family analysis showed that Asp31Asn and Thr591Lys were coallelic and maternally transmitted while Trp157Arg was transmitted by the father, and a genomic screen of 100 healthy individuals ruled out frequent polymorphisms. Mutational analysis indicated wild-type activity for the Asp31Asn carboxylase. In contrast, the respective Trp157Arg and Thr591Lys activities were 8% and 0% that of wild-type carboxylase, and their compound heterozygosity can therefore account for functional VKD factor deficiency. The implications for carboxylase mechanism are discussed. |
| Databáze: | OpenAIRE |
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