Identification of four novel mutations in F5 associated with congenital factor V deficiency

Kanaji, Sachiko; Kanaji, Taisuke; Honda, Miho; Nakazato, Sachie; Wakayama, Kazuo; Tabata, Yoshitomi; Shibata, Shoichiro; Gondo, Hisashi; Nakamura, Ikuko; Node, Koichi; Miura, Motoki; Miyahara, Masaharu; Okamura, Takashi; Nagumo, Fumio; Izuhara, Kenji

doi:10.1007/s12185-008-0210-4

Cited by 6 publications

(5 citation statements)

References 19 publications

(18 reference statements)

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“…In summary, we investigated the p.Phe218Ser and p.Gly304Glu missense mutations of the F5 gene in 2 Chinese families, in which the p.Phe218Ser mutation was previously reported by Kanaji et al [15]. In our study, we revealed that the p.Phe218Ser and p.Gly304Glu F5 variants are probably deleterious and responsible for the reduction in FV:C and FV:Ag levels.…”

Section: Discussionsupporting

confidence: 63%

Significance of the p.Phe218Ser and p.Gly304Glu F5 Variants in Hereditary Factor V Deficiency

et al. 2021

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Hereditary factor V (FV) deficiency is a rare autosomal recessive bleeding disorder caused by <i>F5</i> gene mutations. The objective of this study was to investigate the p.Phe218Ser and p.Gly304Glu variants found in 2 families with hereditary FV deficiency. The FV activity (FV:C) and FV antigen (FV:Ag) were measured by clotting and ELISA, respectively. The <i>F5</i> gene and sequence conservation were analyzed by direct sequencing and ClustalX-2.1-win, respectively. One proband carried a homozygous p.Phe218Ser (c.653T>C) mutation, with FV:C and FV:Ag decreased to 11 and 14%, respectively. The other proband carried a heterozygous p.Gly304Glu (c.911G>A) mutation, with FV:C and FV:Ag reduced to 55 and 62%, respectively. Phe218 and Gly304 were highly conserved in the homologous gene in 9 other species. We hypothesized that the p.Phe218Ser and p.Gly304Glu variants are deleterious and responsible for the reduction in FV:C and FV:Ag.

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Section: Discussionsupporting

confidence: 63%

Significance of the p.Phe218Ser and p.Gly304Glu F5 Variants in Hereditary Factor V Deficiency

et al. 2021

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“…Considering the mutation of F5 in this patient, there were no detectable levels of FV antigens in plasma, whereas, FV protein was weakly detected in platelet lysate 5 . In this study, F5 mRNA expression level in F5 (mut/mut) HLCs was similar to that of positive control in this study (Figure 3C).…”

Section: Discussionsupporting

confidence: 77%

“…Coagulation tests before surgery revealed that prothrombin time‐International Normalized Ratio (PT‐INR) was 4.41 and activated partial thromboplastin time (APTT) was 133.2 seconds (27.0‐43.0 seconds). A blood test showed that FV clotting activity was <3% (normal range: 70%‐135%) and FV antigen was less than 2% (normal average: 60%‐150%) as previously reported 5 . The study protocol was reviewed and approved by the institutional review board of the Ethics Committee of the Kurume University School of Medicine, and the patient signed an informed consent form in accordance with the Helsinki Declaration.…”

Section: Methodsmentioning

confidence: 54%

Successful correction of factor V deficiency of patient‐derived iPSCs by CRISPR/Cas9‐mediated gene editing

et al. 2020

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Coagulation factor V (FV) deficiency, also known as parahaemophilia, is a rare bleeding disorder, with frequency is estimated as one case per million people. FV deficiency can be classified as (a) type I deficiency, or cross-reacting material negative (CRM-) defect, with concordantly low or unmeasurable antigen and functional level (quantitative defect); (b) type II deficiency, or CRM+ defect, with normal or mildly reduced antigen level associated with reduced coagulant activity (qualitative defect). 1 FV deficiency is usually asymptomatic, whereas some patients with a low FV coagulant activity level may exhibit severe bleeding

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“…Even though their FV defects were caused by the same pathogenic mutation, only two patients presented bleeding symptoms, suggesting a poor association between clinical symptoms of FV deficiency and the location of the mutation. Kanaji et al 19 revealed that the two probands with p.Phe190Ser did not share the same haplotype, and thus inferred that p.Phe190Ser may be a mutational hotspot. In our cohort, however, haplotype analysis revealed the founder effects.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characterization and Molecular Analysis of Fourteen Chinese Patients with Factor V Deficiency

Zhang,

Ye,

Jin

et al. 2023

Hamostaseologie

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Introduction Coagulation factor V (FV) functions as a vital cofactor that performs procoagulant roles in the coagulation system. We investigated 14 unrelated patients whose plasma FV levels were all below the reference range. Methods FV activity (FV:C) and FV antigen were detected by one-stage clotting and ELISA, respectively. All 25 exons of the F5 gene in patients were amplified by the PCR, and they were sequenced directly. Haplotype analysis was performed with different polymorphisms on F5. Protein modeling was applied to analyze the potential molecular mechanisms. Results Of five patients with higher FV levels (FV:C > 10%), only one had minor bleeding symptoms. In contrast, of the remaining eight patients with lower FV levels (FV:C < 10%), six showed various bleeding manifestations. A total of 10 mutations were detected from 14 patients (6 were novel mutations). Interestingly, the homozygous p.Phe190Ser was found in five pedigrees, and haplotype analysis showed that they shared almost the same haplotype, indicating the common origin rather than a hotspot mutation. In silico analysis preliminarily investigated the potential pathogenic mechanism of the mutation. Modeling analysis showed that all six missense mutations would lead to conformational alterations in the FV protein. Among them, three (p.Gly1715Ser, p.Ser1753Arg, and p.Asp68His) would decrease hydrogen bonds. Conclusion This is the largest genetic analysis of a single cohort of FV deficiency in Chinese. The study demonstrated that FV levels tended to be correlated with the probability of hemorrhage. The identification of a large number of unique FV-deficient pedigrees highlighted the screening for mutations in F5.

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Identification of four novel mutations in F5 associated with congenital factor V deficiency

Cited by 6 publications

References 19 publications

Significance of the p.Phe218Ser and p.Gly304Glu F5 Variants in Hereditary Factor V Deficiency

Significance of the p.Phe218Ser and p.Gly304Glu F5 Variants in Hereditary Factor V Deficiency

Successful correction of factor V deficiency of patient‐derived iPSCs by CRISPR/Cas9‐mediated gene editing

Clinical Characterization and Molecular Analysis of Fourteen Chinese Patients with Factor V Deficiency

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