Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization
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 t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-05-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/rth2.12407 |
| _version_ | 1797727512409669632 |
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| author | Aliza Cassel Nurit Rosenberg Emad Muhammad Tami Livnat Rima Dardik Miriam Berl Meir Preis |
| author_facet | Aliza Cassel Nurit Rosenberg Emad Muhammad Tami Livnat Rima Dardik Miriam Berl Meir Preis |
| author_sort | Aliza Cassel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:00:47Z |
| format | Article |
| id | doaj.art-b3b9c4f2f7a74719b869f97c77ef23fe |
| institution | Directory Open Access Journal |
| issn | 2475-0379 |
| language | English |
| last_indexed | 2024-03-12T11:00:47Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj.art-b3b9c4f2f7a74719b869f97c77ef23fe2023-09-02T05:44:08ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792021-05-0154n/an/a10.1002/rth2.12407Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterizationAliza Cassel0Nurit Rosenberg1Emad Muhammad2Tami Livnat3Rima Dardik4Miriam Berl5Meir Preis6Institute of Hematology Carmel Medical Center Haifa IsraelThe Israeli National Hemophilia Sheba Medical CenterTel Hashomer IsraelInstitute of Hematology Carmel Medical Center Haifa IsraelThe Israeli National Hemophilia Sheba Medical CenterTel Hashomer IsraelThe Israeli National Hemophilia Sheba Medical CenterTel Hashomer IsraelInstitute of Hematology Carmel Medical Center Haifa IsraelInstitute of Hematology Carmel Medical Center Haifa IsraelAbstract 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.https://doi.org/10.1002/rth2.12407bleeding disordersfactor VIImutationthrombin generation |
| spellingShingle | Aliza Cassel Nurit Rosenberg Emad Muhammad Tami Livnat Rima Dardik Miriam Berl Meir Preis Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization Research and Practice in Thrombosis and Haemostasis bleeding disorders factor VII mutation thrombin generation |
| title | Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization |
| title_full | Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization |
| title_fullStr | Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization |
| title_full_unstemmed | Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization |
| title_short | Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization |
| title_sort | novel mutation in coagulation factor vii carmel mutation identification and characterization |
| topic | bleeding disorders factor VII mutation thrombin generation |
| url | https://doi.org/10.1002/rth2.12407 |
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