A nonstop mutation in the factor (F)X gene of a severely haemorrhagic patient with complete absence of coagulation FX.
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.
Ameri
Afshin
A
Department of Pediatrics, Division of Hematology and Oncology, Medical College of Georgia, Augusta, Georgia, USA.
Machiah
Deepa K
DK
Tran
Thuy T
TT
Channell
Cynthia
C
Crenshaw
Valerie
V
Fernstrom
Karl
K
Khachidze
Manana
M
Duncan
Alexander
A
Fuchs
Sebastien
S
Howard
Tom E
TE
D024509:3' Flanking Region; D000293:Adolescent; D001483:Base Sequence; D001777:Blood Coagulation; D018388:Codon, Terminator; D004252:DNA Mutational Analysis; D005091:Exons; D005170:Factor X / Q000032:analysis / Q000235:genetics*; D005171:Factor X Deficiency / Q000097:blood / Q000150:complications* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage / Q000097:blood / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020871:RNA Stability; D012333:RNA, Messenger / Q000097:blood*; D012720:Severity of Illness Index
D018388:Codon, Terminator; D012333:RNA, Messenger; D005170:Factor X