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Scientific article
English

Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA)

Contributors

Attanasio, Catia; David, Armelle; Neerman Arbez, Marguerite

Published in

Blood, vol. 101, no. 5, p. 1851-1856

Publication date

2003

Abstract

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.

Keywords

  • Afibrinogenemia/ genetics
  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Exons/genetics
  • Fibrinogen/ genetics
  • Humans
  • Introns/ genetics
  • Models, Genetic
  • RNA Splice Sites
  • RNA Splicing
  • RNA, Messenger/genetics/metabolism

UNIGE affiliation entities

Citation (ISO format)

ATTANASIO, Catia, DAVID, Armelle, NEERMAN ARBEZ, Marguerite. Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA). In: Blood, 2003, vol. 101, n° 5, p. 1851–1856. doi: 10.1182/blood-2002-03-0853

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Article

Identifiers

Additional URL for this publication

http://bloodjournal.hematologylibrary.org/cgi/reprint/101/5/1851.pdf

Journal ISSN

0006-4971
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12/07/2010 11:56:54

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