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

Authors

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

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

Full Text

References

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