Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder

Verena Schroeder; Esther Meili; Trinh Cung; Peter Schmutz; Hans P. Kohler

doi:10.1160/TH05-06-0388

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(01): 77-84
DOI: 10.1160/TH05-06-0388

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder

Verena Schroeder

¹Laboratory for Thrombosis Research, Department of Clinical Research, Inselspital, University Hospital, Bern, Switzerland

,

Esther Meili

²Hemostasis Unit, Division of Hematology, University Hospital, Zurich, Switzerland

,

Trinh Cung

¹Laboratory for Thrombosis Research, Department of Clinical Research, Inselspital, University Hospital, Bern, Switzerland

,

Peter Schmutz

¹Laboratory for Thrombosis Research, Department of Clinical Research, Inselspital, University Hospital, Bern, Switzerland

,

Hans P. Kohler

¹Laboratory for Thrombosis Research, Department of Clinical Research, Inselspital, University Hospital, Bern, Switzerland

› Author Affiliations

Abstract

Summary

In 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 del G, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.

Keywords

Coagulation factor XIII - congenital FXIII deficiency - FXIII Asubunit gene

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References

References
1 Duckert F. et al. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 05: 179-86.
2 Laki K, Lorand L. On the solubility of fibrin clots. Science 1948; 108: 208.
3 Ichinose A. The physiology and biochemistry of factor XIII. In: Haemostasis and Thrombosis. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. eds. 3rd edn. Vol. 1 Edinburgh: Livingstone; 1994: 531-46.
4 Muszbek L. et al. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci 1996; 33: 357-421.
5 Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol 1999; 107: 468-84.
6 Human Gene Mutation Database. http://www.hgmd.org Accessed April 14, 2005.
7 Durrer D. Der congenitale Faktor XIII-Mangel. Eine Darstellung anhand eines Familien-Reports, genealogischer Recherchen und einer kritischen Sichtung der aktualisierten Literatur. Inaugural-Dissertation. University of Zurich; 1999
8 Ariëns RAS. et al. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension. Arterioscler Thromb Vasc Biol 1999; 19: 2012-6.
9 Board P. et al. Identification of a point mutation in factor XIII A subunit deficiency. Blood 1992; 80: 937-41.
10 Mikkola H. et al. Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels. Blood 1994; 84: 517-25.
11 Gómez EBGarcía. et al. Two novel and one recurrent missense mutation in the factor XIII A gene in two Dutch patients with factor XIII deficiency. Br J Haematol 2001; 112: 513-8.
12 National Center for Biotechnology Information. Genbank. http://www.ncbi.nlm.nih.gov/Genbank/GenbankSearch.html
13 Aslam S. et al. Structural analysis of a missense mutation (Val414Phe) in the catalytic core domain of the factor XIII A subunit. Br J Haematol 1997; 98: 346-52.
14 Duan B, Wang X, Chu H. et al. Deficiency of factor XIII gene in Chinese: 3 novel mutations. Int J Hematol 2003; 78: 251-5.
15 Ichinose A. et al. Arg260Cys mutation in severe factor XIII deficiency: conformational change of the A subunit is predicted by molecular modelling and mechanics. Br J Haematol 1998; 101: 264-72.
16 Vreken P. et al. 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. Thromb Haemost 1995; 74: 584-9.
17 Anwar R. et al. New splicing mutations in the human factor XIIIA gene, each producing multiple mutant transcripts of varying abundance. Thromb Haemost 1998; 79: 1151-6.
18 Anwar R. et al. Splicing and missense mutations in the human FXIIIA gene causing FXIII deficiency: effects of these mutations on FXIIIA RNA processing and protein structure. Br J Haematol 1998; 103: 425-8.
19 Kohler HP. et al. A common coding polymorphism in the factor XIII A-subunit gene (FXIIIVal34Leu) affects cross-linking activity. Thromb Haemost 1998; 80: 704.
20 Vysokovsky A. et al. Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families. J Thromb Haemost 2004; 02: 1790-7.