Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene

Abstract

Summary. Factor V (FV) deficiency (parahaemophilia) is an autosomal recessive bleeding disorder with an incidence of 1:10 6 . We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0·3% and <1·6% of normal, respectively). Both parents showed plasma levels of factor V activity of about 50% of normal. Sequence analysis of the 5 0 -and 3 0 -untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13. Subsequent screening of members of the family for the mutation showed that both parents were heterozygous for the mutation, that one healthy sister carried only normal alleles, and that the patient was homozygous for the mutated allele. The mutation introduced a frameshift and a novel premature stop codon in codon 1303, and would predict the synthesis of a truncated factor V molecule that lacks part of the B domain and the complete light chain. However, no factor V heavy chain could be detected in the plasma of the patient. Furthermore, factor V activity could not be detected in the patients' platelets. This is the first reported mutation in the factor V gene that predicts a type I quantitative factor V deficiency. Surprisingly, the patient, who is homozygous for the mutation, so far has only a very mild bleeding tendency.

Severe coagulation factor V deficiency caused by 2 novel frameshift mutations: 2952delT in exon 13 and 5493insG in exon 16 of factor 5 gene

“…The remaining exons were amplified by the use of published primer sequences. 11 PCR products purified by ultrafiltration were sequenced by ABI 310 Genetic Analyzer (Applied Biosystems, Foster City, CA).…”

“…8,9 More than 200 factor V-deficient cases have been reported in the literature, but the molecular basis for factor V deficiency has been established in only a few cases. [10][11][12][13] Additional molecular defects in the factor V gene have been identified in patients with "pseudohomozygosity" for factor V Leiden (the Leiden allele plus the null allele). These patients may be identified on the basis of thrombotic problems (reviewed in Kane 1 ).…”

Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms

“…Despite this important observation, platelet FV is not routinely evaluated in FV-deficient patients and only 3 other studies report platelet FV levels in patients with severe FV deficiency. [32][33][34] No platelet FV antigen or activity could be demonstrated in 2 patients with undetectable plasma FV. 32,33 In another FV-deficient patient, platelet FV could be visualized by Western blotting, but its activity was not determined.…”

Homozygous factor V splice site mutation associated with severe factor V deficiency

“…In the proband, we identified 2 novel homozygous genetic alterations and 17 previously described, clinically innocent polymorphisms (Whitehead cSNP database, http://waldo.wi.mit.edu/cvar_snps/). 6,9,10 From the Department of Pathology, Stanford University School of Medicine, and the Department of Pediatric Hematology, University of California at San Francisco. …”