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. 2021 Feb 25;5(4):e12407.
doi: 10.1002/rth2.12407. eCollection 2021 May.

Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization

Aliza Cassel  1 , Nurit Rosenberg  2   3 , Emad Muhammad  1 , Tami Livnat  2   3 , Rima Dardik  2   3 , Miriam Berl  1 , Meir Preis  1   4
Affiliations

Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization

Aliza Cassel et al. Res Pract Thromb Haemost. .

Abstract

Background: Measurement of factor VII (FVII) activity does not enable prediction of bleeding tendency in individuals with inherited FVII deficiency.

Objective: To characterize the molecular and functional features of FVII in a family with FVII deficiency and correlate them with the bleeding tendency.

Patients/methods: We studied 7 family members with very low FVII activity using prothrombin time (PT), activated factor VII (FVIIa), FVII activity level, and thrombin generation. The factor 7 gene was sequenced and the mutation was analyzed by prediction software.

Results: The proband has very low FVII activity (0%-4%), with PT ranging between 5% to 18% depending on the tissue factor (TF) origin. Direct sequencing demonstrated a single homozygous nucleotide substitution G > A in exon 6, predicting a novel missense mutation Cys164Tyr. Three members of the family were found to be heterozygous carriers of this mutation. One of them was a compound heterozygote, carrying both the Cys164Tyr and Ala244Val mutation (linked to Arg353Gln polymorphism). Her FVII activity and antigen levels were 3%-7% and 8%, respectively. The other heterozygous carriers demonstrated FVII activity of 41%-54%, FVII antigen of 46%-66%, and FVIIa activity of 30%. FVIIa was undetectable in the homozygous and compound heterozygous subjects. Thrombin generation was normal in the presence of calcium, but no response to TF addition was observed in the homozygous proband, and a reduced response was observed in the compound heterozygous subject.

Conclusion: The patient homozygous for the "Carmel" mutation has mild clinical manifestations despite very low FVII activity, which correlates with thrombin generation results.

Keywords: bleeding disorders; factor VII; mutation; thrombin generation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Family pedigree. Gray represents the Cys164Tyr; black represents Ala244Val. ?, not determined; X, not available
Figure 2FactorVII(
Figure 2FactorVII(
FVII) sequencing results. Sanger sequencing results of the new site of mutation in exon 6. Shown are homozygote, heterozygote, and normal control. The G659A exchange is boxed
Figure 3
Figure 3
Thrombin generation was measured in plasma of two members of the family, in the absence (in green) or presence of TF (1 pM in red, 5 pM in blue). A, demonstrates plasma taken from normal control; B, from heterozygote to Carmel mutation with normal TG; and C, demonstrates the TG in plasma taken from homozygotes to Carmel mutation
Figure 4
Figure 4
ConSeq evolutionary conservation analysis of Cys164 FVII protein. Prediction conservation of residues 141‐184 in the mature protein, colored according to evolutionary conservation score. Scale bar for the evolutionary conservation scores is displayed in the bottom. Position 164 marked in square demonstrate the missense mutation. The nature of the residues designated as detailed: e ‐ An exposed residue according to the neural‐network algorithm.b ‐ A buried residue according to the neural‐network algorithm.f ‐ A predicted functional residue (highly conserved and exposed).s ‐ A predicted structural residue (highly conserved and buried)
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