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Results for “Factor XIII Deficiency”

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PubMed1995

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

Factor XIII (FXIII) is a zymogen essential for normal haemostasis. In inherited FXIII deficiency the majority of cases show absence of the FXIIIa 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 FXIII 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.

Base Sequence↗
PubMed1977

Factor XIII deficiency in BALB/c mice with plasmacytoma.

These studies examined the fate of Factor XIII (fibrin-stabilizing factor) in mice with plasmacytoma (MOPC-300, MOPC-384, MOPC-467, and J-558). Plasma Factor XIII levels in these mice decreased progressively with tumor expansion. No plasma inhibitors of Factor XIII activity could be detected. Factor XIII was found on plasmacytoma cell membranes and in the cytoplasm of the malignant cells by immunofluorescence. The inverse relationship between tumor load and plasma Factor XIII levels suggested that the fibrin-stabilizing factor was absorbed by the malignant cells.

Animals↗
PubMed1993

Factor XIII deficiency in Pakistan.

Patients with undiagnosed haemostatic defects seen at The Aga Khan Hospital and Fatimid Blood Transfusion Centre during the period of 7 years (1985-1992) were screened with routine tests including bleeding time (BT), whole blood clotting time (CT), platelet count, activated partial thromboplastin time (APTT), prothrombin time (PT) and 5 molar urea test. Nine patients had a positive 5 molar urea test indicating factor XIII deficiency. Rest of the screening tests were normal in these patients. High incidence of consanguinity was observed in affected families. Clinical features included excessive bleeding from umbilical stump, bruising, post-traumatic bleeding, epistaxis, melaena and intracerebral bleeding. All the patients were treated with fresh frozen plasma and cryoprecipitate.

Adult↗
PubMed2002

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.

Factor XIII↗
PubMed2006

Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States.

A 1967 report described the first known case of congenital factor XIII (FXIII) deficiency in the United States in a male patient with a severe hemorrhagic disorder. The patient's family presented no symptoms of the disorder, but the members were found to have half the normal FXIII activity. Although the molecular basis of the disorder could not be evaluated at the time, the results suggested an autosomal recessive inherited disorder. We sequenced all of the exons and the flanking regions in the genes for the FXIII A and B subunits of the patient, his family, and 18 unrelated individuals. We report the novel combination of an Arg-to-Cys mutation at codon 78 and a G-to-C mutation at the intron 5/exon 6 splice junction in the patient's FXIIIA gene. The missense-splice junction mutation combination appears to have caused the patient's FXIIIA deficiency, because the remaining family members, who present no symptoms and have no clinical diagnoses of FXIII deficiency, have one or the other of the 2 mutations but not both. Additionally, the 18 unrelated individuals are homozygous wild type at these loci. The molecular consequences of these mutations appear to be an abnormality in protein conformation or folding and/or a reduced production of messenger RNA transcripts of varying length that likely result in a nonfunctional, unstable FXIII protein.

Adult↗
PubMed2006

[A novel genetic defect in a Chinese family with inherited coagulation factor XIII deficiency].

OBJECTIVE: To identify the genetic defect of inherited coagulation factor (F) deficiency in a Chinese family and to explore its molecular mechanism. METHODS: The activity and antigen of plasma F were measured by photometric test and enzyme-linked immunosorbent assay, and rocket-electrophoresis, respectively. All the exons and exon-intron boundaries of the FA subunit gene were amplified by PCR and then DNA sequencing was performed. Restriction endonuclease analysis was used for the PCR products of the family members and 80 healthy donors to exclude gene polymorphism. RESULTS: Rapid dissolution of the proband's fibrin clot occurred within 30 minutes, and antigen of his plasma F was significantly decreased, two compound heterozygous missense mutations (a C to T transition at nucleotide 177,246 which caused Arg703Trp, and a A to G transition at nucleotide 177,286 which caused His716Arg) in exon 15 of FA subunit gene were found. The possibility of gene polymorphism was excluded by restriction endonuclease analysing. Each of these two missense mutations was respectively found in his mother and father. Molecular modeling based on 3D crystallographic data predicted that the mutant protein decreased stability and was likely to be rapidly degraded. CONCLUSIONS: The inherited F deficiency in the Chinese family is caused by two compound heterozygous missense mutations-Arg703Trp and His716Arg in the FA subunit, which to our knowledge, are reported for the first time.

Base Sequence↗