A nonstop mutation in the factor (F)X gene of a severely haemorrhagic patient with complete absence of coagulation FX

Afshin Ameri, Deepa K. Machiah, Thuy T. Tran, Cynthia Channell, Valerie Crenshaw, Karl Fernstrom, Manana Khachidze, Alexander Duncan, Sebastien Fuchs, Tom E. Howard

Research output: Contribution to journalArticle

11 Scopus citations

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 T-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.

Original languageEnglish (US)
Pages (from-to)1165-1169
Number of pages5
JournalThrombosis and Haemostasis
Volume98
Issue number6
DOIs
Publication statusPublished - Dec 1 2007

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Keywords

  • Autosomal recessive
  • Congenital bleeding disorder
  • F10-Augusta
  • mRNA surveillance

ASJC Scopus subject areas

  • Hematology

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