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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0853.
Submitted March 19, 2002
Accepted October 15, 2002
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*
Division of Medical Genetics, University Medical Centre, Geneva, Switzerland
Division of Angiology and Hemostasis, University Hospital, Geneva, Switzerland
* Corresponding author; email: marguerite.arbez{at}medicine.unige.ch.
Congenital afibrinogenemia (MIM # 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 FGA intron 4, IVS4+1G>T. Two other FGA donor splice mutations, in intron 1 (IVS1+3A>G) and in intron 3 (IVS3+1_+4 delGTAA) 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 IVS3del GTAA mutation showed exon 3 skipping in 99% of transcripts and exon 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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