Frequencies of mild factor V, VII and X deficiencies in a Japanese population.

We investigated the frequencies of coagulation factor deficiencies in a Japanese population. We measured factor II, V, VII and X activity in 100 healthy individuals. A specific factor deficiency was determined according to the factor activity and the ratio of the factor activity to that of other coagulation factors. Seven samples showed factor activity less than the mean -2SD of standardized factor activity (factor II: three; factor V: one; factor VII: one; factor X: one and factor V+factor VII: one). The samples with low factor II and factor VII activity were determined not to be due to deficiency because the ratios of these factor activities to other factor activities were within the range of the mean +/- 2SD. We measured activity ratios in the remaining 97 samples and identified one sample with factor V deficiency and two with factor VII deficiency. Thus, six samples with coagulation factor deficiency were identified (factor X: one; factor V: two; factor VII: two and factor V + factor VII: one). These results suggest that the Japanese population has relatively high frequencies of mild factor V, factor VII and factor X deficiencies, in which activity is reduced to approximately 50% (36-64%) of normal plasma.

Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency.

The factor V Leiden variant, responsible for the phenomenon of activated protein C resistance, was found to be less frequent among British (0.06) and Swedish/Danish (0.15) protein C deficiency patients than previously reported in a Dutch study (0.19). In the Swedish population, a significantly increased frequency of the factor V Leiden allele was apparent in protein C deficiency patients as compared to healthy controls. However, this was not found in the British population. Coinheritance of the factor V Leiden variant is therefore unlikely to be the sole determinant of whether a person with protein C deficiency will come to clinical attention. Nevertheless, when patient data were analysed by type of protein C deficiency, it was noted that the frequency of the factor V Leiden variant was 2.8-fold higher in type II patients compared to type I patients. A possible explanation of this disparity is discussed.

Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency.

Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factors V and VIII are diminished. The F5F8D locus was previously mapped to a 1-cM interval on chromosome 18q21. Mutations in a candidate gene in this region, ERGIC-53, were recently found to be associated with the coagulation defect in nine Jewish families. We performed single-strand conformation and sequence analysis of the ERGIC-53 gene in 35 F5F8D families of different ethnic origins. We identified 13 distinct mutations accounting for 52 of 70 mutant alleles. These were 3 splice site mutations, 6 insertions and deletions resulting in translational frameshifts, 3 nonsense codons, and elimination of the translation initiation codon. These mutations are predicted to result in synthesis of either a truncated protein product or no protein at all. This study revealed that F5F8D shows extensive allelic heterogeneity and all ERGIC-53 mutations resulting in F5F8D are "null." Approximately 26% of the mutations have not been identified, suggesting that lesions in regulatory elements or severe abnormalities within the introns may be responsible for the disease in these individuals. In two such families, ERGIC-53 protein was detectable at normal levels in patients' lymphocytes, raising the further possibility of defects at other genetic loci.

ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families.

Combined factors V and VIII deficiency is an autosomal recessive bleeding disorder associated with plasma levels of coagulation factors V and VIII approximately 5% to 30% of normal. The disease gene was recently identified as the endoplasmic reticulum-Golgi intermediate compartment protein ERGIC-53 by positional cloning, with the detection of two founder mutations in 10 Jewish families. To identify mutations in additional families, the structure of the ERGIC-53 gene was determined by genomic polymerase chain reaction (PCR) and sequence analysis of bacterial artificial chromosome clones containing the ERGIC-53 gene. Nineteen additional families were analyzed by direct sequence analysis of the entire coding region and the intron/exon junctions. Seven novel mutations were identified in 10 families, with one additional family found to harbor one of the two previously described mutations. All of the identified mutations would be predicted to result in complete absence of functional ERGIC-53 protein. In 8 of 19 families, no mutation was identified. Genotyping data indicate that at least two of these families are not linked to the ERGIC-53 locus. Taken together, these results suggest that a significant subset of combined factors V and VIII deficiency is due to mutation in one or more additional genes.