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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0853.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1851-1856
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Outcome of donor splice site mutations accounting for congenital
afibrinogenemia reflects order of intron removal in the fibrinogen
alpha gene (FGA)
Catia Attanasio,
Armelle David, and
Marguerite Neerman-Arbez
From the Division of Medical Genetics, University
Medical School and University Hospital, Geneva,
Switzerland, and the Division of Angiology and Hemostasis,
University Hospital, Geneva, Switzerland.
Congenital afibrinogenemia (Mendelian Inheritance in Man
#202400) is a rare, autosomal recessive disorder characterized by the
complete absence of circulating fibrinogen. Our recent studies on the
molecular basis of the disease showed that the most common genetic
defect is a donor splice mutation in fibrinogen alpha gene (FGA)
intron 4, IVS4+1G>T. Two other FGA donor splice
mutations, in intron 1 (IVS1+3A>G) and intron 3 (IVS3+1_+4delGTAA),
were identified in afibrinogenemia patients. Because it was impossible to directly study the effect of these mutations on mRNA splicing in
patient hepatocytes, we used a transfected cell approach, which previously allowed us to show that the common IVS4 mutation causes afibrinogenemia due to the activation of multiple cryptic donor splice
sites. In this study, analysis of the IVS3delGTAA mutation showed exon
3 skipping in 99% of transcripts and exons 2 and 3 skipping in 1% of
transcripts. The different outcomes of these donor splice mutations
appear to follow the model proposed in a study of fibrillar collagen
genes, where donor splice mutations occurring in a rapidly spliced
intron with respect to upstream introns lead in most cases to exon
skipping, while mutations in later-spliced introns lead to intron
inclusion or cryptic splice-site utilization. Indeed, we found that in
FGA intron 3 was preferentially spliced first, followed by
intron 2, intron 4, and intron 1.
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