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Genetic analysis and functional characterization of prothrombins Corpus
Christi (Arg382-Cys), Dhahran (Arg271-His), and hypoprothrombinemia
AS O'Marcaigh, WL Nichols, NL Hassinger, JD Mullins, AA Mallouh, GS Gilchrist and WG Owen
Section of Pediatric Hematology, Mayo Clinic and Foundation, Rochester, MN
55905, USA.
The structural abnormalities and functional characteristics of
dysfunctional prothrombin variants in two new kindreds have been
determined. Prothrombin Corpus Christi (family 1) was purified and found to
have markedly reduced fibrinogen clotting activity, yet normal amidolytic
and near-normal platelet aggregating activity. A transition (C to T) at
nucleotide position 8885, present in the heterozygous form in affected
family members, resulted in the substitution of Cys for Arg 382. This
substitution results in the loss of a positive charge within the
fibrinogen-binding exosite of thrombin, thus accounting for the observed
functional defect. A heterozygous C to T transition was also present at
position 19994 in other family members with a hypoprothrombinemic
phenotype. This mutation results in the replacement of Gln 541 (CAA) by a
premature stop codon (TAA). Prothrombin Dhahran (family 2) was found to
have markedly reduced fibrinogen clotting activity, but normal amidolytic
activity. Affected family members were found to have a G to A transition at
nucleotide position 7312 resulting in the substitution of His for Arg 271.
This substitution results in the abolition of a factor Xa cleavage site,
yielding meizothrombin rather than thrombin, on activation of prothrombin
Dhahran by factor Xa. All but one of the above mutations occur at CpG
dinucleotides, thus further supporting the observation of a high incidence
of CpG transitions in hereditary dysprothrombinemia. The significant
bleeding tendencies of individuals homozygous for prothrombin Dhahran
(prothrombin clotting activity 5% to 7%) contrast sharply with the absence
of significant chronic bleeding in the proband expressing prothrombin
Corpus Christi (prothrombin clotting activity 2%). Our findings underscore
the capacity of thrombin to contribute to clinical hemostasis by mechanisms
other than its fibrinogen clotting activity.
Volume 88,
Issue 7,
pp. 2611-2618,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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