Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families.

In this report we describe the molecular basis of FXIII a-subunit deficiency in three unrelated Palestinian Arab families. In three patients representing each family two substitutions were identified in exon 14 on both alleles: C to G change resulting in a Gln651Glu substitution (a previously described polymorphism) and a T to C transition causing Leu660Pro substitution. The latter is a new mutation which creates a restriction site for FnuDII enzyme. Restriction analysis performed in members of the three families clearly distinguished between severely affected patients, obligate carriers and unaffected subjects. A population survey failed to detect the mutation among 250 Jewish individuals but did detect two heterozygotes among 300 Arabs suggesting a 0.0033 frequency for the Pro660 allele in this population. In two out of the three families the Pro660 allele was linked to allele 5 of the 5' short tandem repeat polymorphism within the FXIII a-subunit gene suggesting that the mutation might have occurred at least twice. cDNA obtained from mRNA isolated from patients' platelets and monocytes appeared similar in size to that of normal control indicating that the Leu660Pro mutation does not affect mRNA synthesis. Computer modeling based on cristallographic studies of the a-subunit of factor XIII predicted that the mutant protein is expected to misfold into a structure which is either unstable or susceptible to degradation.

Gene defects in congenital factor XIII deficiency.

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.