1. A nonstop mutation in the factor (F)X gene of a severely haemorrhagic patient with complete absence of coagulation FX.
- Author
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Ameri A, Machiah DK, Tran TT, Channell C, Crenshaw V, Fernstrom K, Khachidze M, Duncan A, Fuchs S, and Howard TE
- Subjects
- 3' Flanking Region, Adolescent, Base Sequence, Blood Coagulation, Codon, Terminator, DNA Mutational Analysis, Exons, Factor X analysis, Factor X Deficiency blood, Factor X Deficiency genetics, Genetic Predisposition to Disease, Hemorrhage blood, Homozygote, Humans, Male, Molecular Sequence Data, Pedigree, Phenotype, Polymerase Chain Reaction, Severity of Illness Index, Factor X genetics, Factor X Deficiency complications, Hemorrhage genetics, Mutation, RNA Stability, RNA, Messenger blood
- Abstract
We identified a previously unknown mutation by sequencing the factor (F)X gene in a severely haemorrhagic 14-year-old male African-American individual with undetectable plasma FX-activity and -antigen levels. This mutation, called F10-Augusta, was homozygote and is a combination of an 8bp insertion in flanking 3'-genomic-DNA and a 5bp terminal exon-8 deletion involving codons 437 and 438. Sequencing of RT-PCR and 3'-RACE products showed that the F10-Augusta transcript is normally processed but lacks an in-frame stop codon. An allele specific 3'-RACE-based RFLP assay demonstrated that the steady-state concentration of the mutant transcript was markedly lower than that of the wild-type message in total-RNA samples from the patient's unaffected heterozygous parents. The recently discovered nonstop decay mechanism, a component pathway of the mRNA surveillance system, is a possible explanation for the reduced concentration of the mutant FX transcript. This is the first report implying such a mechanism in the pathogenesis of inherited bleeding disorders.
- Published
- 2007
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