Factor XIII deficiency: new nonsense and deletion mutations in the human factor XIIIA gene.

We identified five disease-causing mutations in six factor XIII deficient patients from four unrelated families: two novel nonsense mutations (nucleotide 979C-->T corresponding to Arg326Stop; and nucleotide 2075G-->A corresponding to Trp691 Stop), one novel deletion of a single nucleotide (nucleotide 708G or 709G), one previously reported missense mutation (nucleotide 888C-->G corresponding to Ser295Arg), and a previously reported splice site mutation (nucleotide 319G-->T at the last position of exon 3). The phenotypic consequences of these mutations are discussed.

Delayed umbilical bleeding--a presenting feature for factor XIII deficiency: clinical features, genetics, and management.

OBJECTIVES: The objectives of this study were 1) to assess the importance of an early diagnosis for factor XIII (FXIII) deficiency, and 2) to investigate the molecular basis and mechanism(s) of disease in the patients under study. METHODS: The case histories of 6 FXIII-deficient patients were examined to assess the influence of early versus delayed diagnosis and replacement therapy. The nucleotide sequence of the FXIIIA gene was determined to identify the underlying mutations responsible for the bleeding diathesis in each patient. Molecular modeling was used to predict the mechanism(s) of disease causation for each mutation. RESULTS: All cases presented with umbilical hemorrhage. Patients 1 to 3 were diagnosed, and their prophylactic therapy was commenced in infancy. Diagnosis in patients 4 to 6 was considerably delayed and, as a result, they continued to suffer from many bleeding symptoms. The FXIIIA gene mutations identified in these patients were as follows: a homozygous GAA-->AAA mutation in codon 102 (Glu102Lys) in patient 1 and a homozygous AGC-->AGG mutation in codon 295 (Ser295Arg) in patients 2 to 6. These mutations segregate with disease and are absent from the normal population, suggesting that they are likely to be disease-causing sequence changes. Computer modeling indicates that both the Lys102 and Arg295 mutants are unable to fold correctly, and probably result in unstable FXIIIA molecules. CONCLUSIONS: We demonstrate the importance of recognizing delayed umbilical hemorrhage as a presenting feature for congenital FXIII deficiency, and the value of early diagnosis and prophylaxis. The bleeding disorder of patient 1 was attributable to a homozygous Glu102Lys mutation in FXIIIA. A homozygous Ser295Arg mutation in FXIIIA was responsible for FXIII deficiency in patients 2 to 6.