Characterization of a Cys329Gly Mutation Causing Hereditary Factor VII Deficiency

Wu, Yuping; Tu, Xiangdong; Lian, Yunzong; Chen, Feng; Lan, Fenghua; Zhu, Zhongyong

doi:10.1159/000093638

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…Pedigrees with Cys329Gly 25,26 and Cys329Arg 27 mutations have been reported previously, in which the levels of FVII antigens were reduced in all patients, with even lower levels of FVII activity. In vitro studies indicated that Cys329Gly had little effect on the synthesis and secretion of FVII, although the coagulation activity of the mutant protein was almost undetectable 28 . Ser339 was another novel mutation site detected in proband 1, which resulted in a primary aliphatic hydroxy in the catalytic domain of FVII protein; thus, mutations in this site could affect the activity of FVII correspondingly.…”

Section: Discussionmentioning

confidence: 96%

“…In the meantime, SIFT-based investigations showed all three variants is functionally damaging, while the PolyPhen-2 software program indicated the alternation of Ser339 and Gly156 is probably damaging while the replacement by Ser84 is possibly damaging to the newly synthesized protein little effect on the synthesis and secretion of FVII, although the coagulation activity of the mutant protein was almost undetectable. 28 Ser339 was another novel mutation site detected in proband 1, which resulted in a primary aliphatic hydroxy in the catalytic domain of FVII protein; thus, mutations in this site could affect the activity of FVII correspondingly.…”

Section: Discussionmentioning

confidence: 99%

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Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Zhang

Wang

Leng

et al. 2021

Clinical Laboratory Analysis

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Introduction Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. Methods We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. Results In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5′ untranslated region (UTR) was closely associated with the mRNA regulatory sequence. Conclusion We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Zhang

Wang

Leng

et al. 2021

Clinical Laboratory Analysis

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“…All the patients in these reports had decreased FVII antigen and much lower FVII activity compared to the level of the FVII antigen. An in vitro study, which was carried out to investigate the effect of Cys329Gly, showed that the mutation had little affection on the FVII synthesis and secretion while the coagulation activity of the mutated protein was almost undetectable [15].…”

Section: Discussionmentioning

confidence: 99%

Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigree

Wang

Ding

et al. 2009

Haemophilia

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Factor VII deficiency which transmitted as an autosomal recessive disorder is a rare haemorrhagic condition. The aim of this study was to identify the molecular genetic defect and determine its functional consequences in a Chinese pedigree with FVII deficiency. The proband was diagnosed as inherited coagulation FVII deficiency by reduced plasma levels of FVII activity (4.4%) and antigen (38.5%). All nine exons and their flanking sequence of F7 gene were amplified by polymerase chain reaction (PCR) for the proband and the PCR products were directly sequenced. The compound heterozygous mutations of F7 (NM_000131.3) c.572-1G>A and F7 (NM_000131.3) c.1165T>G; p.Cys389Gly were identified in the proband's F7 gene. To investigate the splicing patterns associated with F7 c.572-1G>A, ectopic transcripts in leucocytes of the proband were analyzed. F7 minigenes, spanning from intron 4 to intron 7 and carrying either an A or a G at position -1 of intron 5, were constructed and transiently transfected into human embryonic kidney (HEK) 293T cells, followed by RT-PCR analysis. The aberrant transcripts from the F7 c.572-1G>A mutant allele were not detected by ectopic transcription study. Sequencing of the RT-PCR products from the mutant transfectant demonstrated the production of an erroneously spliced mRNA with exon 6 skipping, whereas a normal splicing occurred in the wide type transfectant. The aberrant mRNA produced from the F7 c.572-1G>A mutant allele is responsible for the factor VII deficiency in this pedigree.

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“…The mutation occurs in the exon 5 of F7 gene and alters residue 91 in EGF2 (EGF-like 2) domain of the protein. The EGF-like and the serine protease domains are necessary for FVII and TF interaction [64] . Previous studies have also shown that EGF2 mutations dramatically impair FVII coagulant activity by affecting protein-protein interactions [18,54] .…”

Section: Spcd G420vmentioning

confidence: 99%

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

Shahbazi¹,

Mahdian²

2019

ibj

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Coagulation factors belong to a family of plasma glycosylated proteins that should be activated for appropriate blood coagulation. Congenital deficiencies of these factors cause inheritable hemorrhagic diseases. Factor VII (FVII) deficiency is a rare bleeding disorder with variable clinical symptoms. Various mutations have been identified throughout the F7 gene and can affect all the protein domains. The results of previous experiments have partly revealed the correlation between genotype and phenotype in patients with FVII deficiency. Nevertheless, each particular variant may affect the coagulative function of FVII, mainly via altering its expression level, extra-cellular secretion, tissue factor binding affinity, or proteolytic activity. The pathogenicity of the variants and molecular mechanisms responsible for clinical symptoms in patients with FVII deficiency should be characterized via in silico and in vitro, as well as in vivo functional studies. This review has highlighted the most important functional studies reported on F7 gene variants, including relevant reports regarding Iranian FVII deficiency patients.

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Characterization of a Cys329Gly Mutation Causing Hereditary Factor VII Deficiency

Cited by 4 publications

References 30 publications

Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigree

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

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