Krzysztof J. A. Miloszewski

Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function

Summary. Factor XIII (FXIII) is a zymogen essential for normal haemostasis. In inherited FXIII deficiency the majority of cases show absence of the FXHIa subunit. Molecular analysis of PCR‐amplified FXIIIa subunit exonic regions, and of RT‐PCR amplified cDNA from six patients with FXIIIa subunit deficiency, from five unrelated families, has revealed 10 sequence changes: three mutations resulting in abnormal splicing of pre‐mRNA, one nonsense mutation, one deletion/insertion change, three point mutations producing Val34Leu, Asn60Lys and Arg408Gln changes, and two silent mutations. In three families the patients are homozygous for a specific deficiency causing mutation, and patients from the remaining two families are compound heterozygotes. Understanding the molecular pathology of the disorder provides insights into the structure‐function relationships of the various domains within the FXm protein. From a clinical point of view, it enables direct diagnosis at the DNA level and may aid the development of FXIII analogues to promote wound healing.

Annotation: FACTOR XIII

In 1944 Robbins showed that the action of thrombin on purified fibrinogen, in the presence of calcium ions, produces a clot which is zelatively soluble, unless a small amount of plasma is also present. The factor responsible for the formation of insoluble clot is now known as factor XIII. This term is replacing others, the most popular of which has been Fibrin Stabilizing Factor (FSF). The first convincing demonstration of disease related to factor XI11 was the description of congenital, inherited deficiency by Duckert et a f in 1960.

An Acquired Inhibitor of Factor XIII with a Qualitative Abnormality of Fibrin Cross-Linking

A patient with an acquired inhibitor to factor XIII is reported. The patients plasma produced a profound inhibition of factor XIII activity in normal plasma measured by a dansylcadaverine casein assay and stimulated a very abnormal pattern of fibrin cross-linking, not normally seen with factor XIII. Partial characterisation of the inhibitor suggests that it is heat stable and not an immunoglobulin.

Splicing and missense mutations in the human FXIIIA gene causing FXIII deficiency : effects of these mutations on FXIIIA RNA processing and protein structure

We have investigated the molecular basis of factor XIII (FXIII) deficiency in a family from the north‐west region of the U.K. and identified two sequence changes in the FXIII subunit A (FXIIIA) gene. We report a novel Asn to Lys mutation at codon 541, and a g → a mutation at the intron 5/exon 6 splice junction in the FXIIIA gene. The splicing mutation results in two abnormal FXIIIA transcripts. The Asn541 residue is important for stabilizing an external fold in the FXIIIA barrel 1 domain. The Asn541Lys mutation is expected to result in inappropriate folding and therefore an unstable FXIIIA molecule.

Fibrinolysis and Factor XIII

Factor XIII levels are within the normal range in patients with pathological fibrinolysis and remain unchanged in the intense fibrinolytic state induced by streptokinase infusion. Incubation of plasma

Fibrinogen/Fibrin Degradation Products and Factor XIII

The effect of fibrinogen/fibrin degradation products (FDP) on the stabilisation of fibrin was tested in vitro by the clot solubility assay and by the transamidase assay of 14