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Thromb Haemost 1995; 74(02): 584-589
DOI: 10.1055/s-0038-1649779
Original Article
Clinical Studies
Schattauer GmbH Stuttgart

A Point Mutation in an Invariant Splice Acceptor Site Results in a Decreased mRNA Level in a Patient with Severe Coagulation Factor XIII Subunit A Deficiency

Peter Vreken
1   The Department of Clinical Chemistry, Center for Hemostasis, Thrombosis, Atherosclerosis, Amsterdam, The Netherlands
,
René W L M Niessen
2   Inflammation Research, Academic Medical Center, Amsterdam, The Netherlands
,
Marjolein Peters
3   The Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands
,
Marianne C L Schaap
4   The Department of Clinical Chemistry, Academic Hospital, Leiden, The Netherlands
,
Johanna G M Zuithoff-Rijntjes
3   The Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands
,
Augueste Sturk
4   The Department of Clinical Chemistry, Academic Hospital, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 08 August 1994

Accepted after resubmission 14 March 1995

Publication Date:
04 September 2018 (online)

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Summary

Amplification and sequencing of exons I-XV of the gene encoding subunit A of coagulation factor XIII (FXIII) in a patient with severe subunit A deficiency revealed a single G → A base substitution at the last position of intron E, mutating the invariant AG dinucleotide splice acceptor site to AA. Northern blot analysis of FXIII subunit A mRNA levels in peripheral mononuclear leukocytes showed that this mutation leads to an undetectable FXIII subunit A mRNA level, suggesting that the mutant transcript is either highly unstable or only spliced at low efficiency. Despite this low mRNA level we were able to amplify cDNA fragments containing the exonV-exonVI junction. Sequence analysis showed that the AA dinucleotide is not recognized by the splicing machinery. Instead, an AG dinucleotide located seven bases downstream of the mutated splice acceptor site is used as alternative acceptor. The resulting, alternatively spliced, FXIII subunit A transcript contains a deletion of the first seven bases of exon VI, while translation continues out of frame and leads to a premature stop codon 27 bases thereafter.

 

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