This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ivaskevicius, V. Articles by Oldenburg, J. PubMed PubMed Citation Articles by Ivaskevicius, V. Articles by Oldenburg, J.

Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function

¹ Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
² Hemostasis Research Laboratory, Department of Hematology, University of Bern, Switzerland
³ Laboratory and Ambulance for Coagulation Disorders, Duisburg, Germany
⁴ Hematology Oncology Center, Munich, Germany
⁵ Pediatric Hospital, University of Leipzig, Leipzig, Germany
⁶ German Clinic for Diagnostic, Wiesbaden, Germany
⁷ Institute of Clinical Genetics, Oberhausen, Germany

Correspondence: Vyatautas Ivaskevicius, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53127 Bonn, Germany. Phone: international +49.0228.287.15175. Fax: international +49.0228.287.16087. E-mail: vytautas.ivaskevicius{at}ukb.uni-bonn.de

ABSTRACT

Background: Severe hereditary coagulation factor XIII (FXIII) deficiency is a rare homozygous bleeding disorder affecting 1 in 2 million individuals. In contrast, heterozygous FXIII deficiency is more common, but usually not associated with severe haemorrhage such as intracranial bleeding and haemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer.

Design and Methods: We analysed ten index patients and three relatives for FXIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the local wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations.

Results: All individuals except one were heterozygous for FXIIIA mutations (average FXIII activity 51%), while the remaining homozygous individual was found to have severe FXIII deficiency (<5% of normal FXIII activity). Eight of 12 heterozygous patients exhibited a bleeding tendency upon provocation.

Conclusions: The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for FXIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on FXIIIA protein structure. Future in vitro expression studies for these FXIII mutations are required to confirm their pathological mechanisms.

Key words: Factor XIII deficiency, FXIII-A, FXIII-B, Structural analysis.