FACTOR-XIII DEFICIENCY DUE TO A LEU660PRO MUTATION IN THE FACTOR-XIIISUBUNIT-A GENE IN 3 UNRELATED PALESTINIAN ARAB FAMILIES

In this report we describe the molecular basis of FXIII a-subunit defi ciency 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 r estriction site for FnuDII enzyme. Restriction analysis performed in m embers of the three families clearly distinguished between severely af fected patients, obligate carriers and unaffected subjects. 4 populati on survey failed to detect the mutation among 250 Jewish individuals b ut did detect two heterozygotes among 300 Arabs suggesting a 0.0033 fr equency for the Pro660 allele in this population. In two out of the th ree 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 fr om mRNA isolated from patients' platelets and monocytes appeared simil ar in size to that of normal control indicating that the Leu660Pro mut ation does not affect mRNA synthesis. Computer modeling based on crist allographic studies of the a-subunit of factor XIII predicted that the mutant protein is expected to misfold into a structure which is eithe r unstable or susceptible to degradation.