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Gene defects in congenital factor XIII deficiency
1Department of Clinical Chemistry, Helsinki University Central Hospital, Finland.
Abstract:
The knowledge of the molecular basis of factor XIII deficiency has improved significantly in recent years. Almost 20 different mutations have been described in the gene coding for the factor A-subunit and 3 mutations in the gene coding for the B-subunit. Half of the mutations in the factor XIIIa A-subunit gene are nonsense mutations that result in premature termination of translation. Three of them are frameshift mutations that are caused by minor deletions. Two of them are splicing mutations and 3 are stop mutations that are caused by single nucleotide substitutions. Ten of the mutations are missense mutations caused by nucleotide transitions leading to amino acid substitutions. In the factor XIII B-subunit gene, the 3 mutations are an amino acid substitution, a splicing mutation, and a trinucleotide insertion. These mutations explain the disease in the two families reported to have XIII B-subunit deficiency. In factor XIII A-subunit deficiency, the genetic defects have been characterized so far only in a minority of cases. In most of the reports of factor XIII A-subunit mutations, each family carries its own mutation/mutations. However, in some populations such as Finns and Arabs some enrichment of specific mutations has occurred. Some international migration of a few mutations has also been noted. The structural and functional effects of the mutations have been analyzed by studying the expression of the factor XIII subunits on mRNA and protein levels in vivo or in vitro, and by utilizing the three-dimensional model of crystallized factor XIII A-subunit in modeling of the missense mutations.
Insights
Recent advances reveal over 20 mutations in factor XIII A-subunit and 3 in B-subunit genes, explaining deficiency causes. Genetic defects are identified in most factor XIII deficiency cases.
Area of Science:
- Molecular genetics
- Hematology
- Biochemistry
Background:
- Factor XIII deficiency is a rare bleeding disorder.
- Understanding its molecular basis is crucial for diagnosis and treatment.
- Recent research has significantly advanced knowledge of genetic defects.
Purpose of the Study:
- To review and summarize the known mutations in the genes encoding factor XIII subunits.
- To discuss the impact of these mutations on protein structure and function.
- To highlight the current state of knowledge regarding the genetic basis of factor XIII deficiency.
Main Methods:
- Literature review of reported mutations in factor XIII A- and B-subunit genes.
- Analysis of mutation types (nonsense, frameshift, splicing, stop, missense, insertion).
- Inclusion of studies analyzing mRNA/protein expression and 3D modeling for functional impact assessment.
Main Results:
- Over 20 mutations identified in the factor XIII A-subunit gene, with half being nonsense mutations.
- 3 mutations identified in the factor XIII B-subunit gene, explaining deficiency in reported families.
- Most factor XIII A-subunit mutations are unique to families, with some population-specific enrichment and international migration.
- Structural and functional effects analyzed via expression studies and 3D modeling.
Conclusions:
- Significant progress has been made in understanding the molecular basis of factor XIII deficiency.
- A wide spectrum of mutations in both A- and B-subunit genes contribute to the disorder.
- Further characterization of genetic defects in factor XIII A-subunit deficiency is ongoing.