Gene Defects in Congenital Factor XIII Deficiency

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.

Factor Xiii Deficiency

“…Since then molecular genetic analysis has demonstrated that FXIII deficiency is a highly heterogenous disorder. The gene defects causing FXIII deficiency were last summarized by Mikkola & Palotie (1996). The number of mutations responsible for FXIII deficiency has more than doubled since then.…”

Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia

“…3,4 In more than 30 unrelated patients the genetic defect(s) responsible for severe FXIII deficiency have been identified. 5,6 In addition to pathogenic mutations, a number of polymorphisms have been identified in the amino acid sequence of FXIII-A. [7][8][9][10] The biochemical effect of these polymorphisms has not been explored.…”

Factor XIII Deficiency: Pathogenic Mechanisms and Clinical Significance

“…In the last few years several research teams have elucidated the genetic defects causing factor XIII defi ciency. [24][25][26][27][28][29][30] Up to now 10 missense, 6 nonsense muta tions, and 2 splicing defects have been found. In homo zygous patients all mutations caused failure of translation and expression of factor XIII subunit A.…”