F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency

2017 ◽  
Vol 117 (08) ◽  
pp. 1455-1464 ◽  
Author(s):  
Gabriele Quintavalle ◽  
Federica Riccardi ◽  
Gianna Rivolta ◽  
Davide Martorana ◽  
Caterina Di Perna ◽  
...  
Keyword(s):  
Diagnostic Testing ◽  
Autosomal Recessive Inheritance ◽  
Large Cohort ◽  
Factor Vii ◽  
Common Mechanism ◽  
Poor Correlation ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Large Deletions ◽  
Fvii Deficiency

SummaryCongenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. It was the objective of this study to identify genetic defects and to evaluate their relationships with phenotype in a large cohort of patients with FVII:C<50%. One hundred twenty-three probands were genotyped for F7 mutations and three polymorphic variants and classified according to recently published clinical scores. Forty out of 123 patients (33?%) were symptomatic (43 bleedings). A severe bleeding tendency was observed only in patients with FVII:C<0.10%. Epistaxis (11%) and menorrhagia (32% of females in fertile age) were the most frequent bleedings. Molecular analysis detected 48 mutations, 20 not reported in the F7 international databases. Most mutations (62%) were missense, large deletions were 6.2%. Compound heterozygotes/homozygotes for mutations presented lower FVII:C levels compared to the other classes (Chi2=43.709, p<0,001). The polymorphisms distribution was significantly different among the three F7 genotypic groups (Chi2=72.289, p<0,001). The presence of truncating mutations was associated with lowest FVII:C levels (Chi2=21.351, p=0.002). This study confirms the clinical and molecular variability of the disease and the type of symptoms. It shows a good correlation between the type of F7 mutation and/or polymorphisms and FVII:C levels, without a direct link between FVII:C and bleeding tendency. The results suggest that large deletions are underestimated and that they represent a common mechanism of F7 gene inactivation which should always be investigated in the diagnostic testing for FVII deficiency.

scholarly journals Genotype-Phenotype Relationship Among 1200 Unrelated White Patients with Inherited FVII Deficiency: A Three-Center Database Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 589-589
Author(s):  
Susan Halimeh ◽  
Gili Kenet ◽  
Piotr Kuta ◽  
Maria Shneyder ◽  
Tido Bajorat ◽  
...  
Keyword(s):  
Blood Group ◽  
Research Funding ◽  
Laboratory Data ◽  
Factor Vii ◽  
Poor Correlation ◽  
Severe Bleeding ◽  
Symptomatic Disease ◽  
Fvii Deficiency ◽  
Work Up ◽  
White Patients

Abstract Background: Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. Aim of this study was to identify genetic defects and to evaluate their relationships with clinical phenotype in a large cohort of 1228 white patients with FVII:C below the age-dependent cut-off %. Methods: Probands with confirmed inherited factor VII deficiency were i) genotyped (Sanger method & multiplex ligation-dependent probe amplification [MLPA]) for F7 mutations including common polymorphic variants and were ii) classified according to clinical bleeding scores (BC). In addition, common thrombophilic variants and blood groups were determined. Results: Probands included asymptomatic subjects (referred for laboratory work up of recurrent prolonged prothrombin time; n=415; mean age 30 + 19 yrs.; female 52%) and patients who presented with mild, moderate or severe bleeding episodes (n=805; mean age 34 + 18 yrs.; female 70%). Bleeding symptoms included epistaxis, gum bleeding, GI bleeding, hematuria, postoperative and gynecologic hemorrhage. Median FVII activity (entire cohort) measured with clotting-based assays (ACL TOP 750 and/or BCS-XP) was 49% (range 5-78%) and the median ISTH BS recorded within a period of two years prior to work-up was 1(0-17). The latter was significantly higher in women compared with males (2 versus 1; p &lt; 0.001). The corresponding PBAC-Score prior to hormonal treatment was 163 (25-1200). Blood group 0 was present in 40.6% of cases. Known and novel mutations in the F7 gene, including coding regions, exon/intron boundaries and the promoter region, are found in 534 patients (44%) and common polymorphisms were detected in 666 subjects (95%). Logistic regression analysis adjusted for clinical and laboratory data (blood group, FVII activity, presence of F7 gene mutations and /or polymorphisms, thrombophilia status and further factor deficiencies) revealed that older age (increase per year) at referral (odds/95% CI: 1.01/1.007-1.025) and female gender (odds/95% CI: 3.25/2.35-4.50) in part explain differences in clinical bleeding phenotype associated with FVII deficiency. Conclusion: Overall there is poor correlation between the FVII level and the bleeding phenotype. Older patients and females are more likely to have symptomatic disease as a result of gynecological or muco-cutaneous bleeding. Disclosures Kenet: Alnylam: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Opko Biologics: Research Funding; Pfizer: Consultancy, Research Funding; Shire: Research Funding; Novo Nordisk: Consultancy; Roche: Consultancy; Takeda: Consultancy.

scholarly journals The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding

2002 ◽  
Vol 88 (10) ◽  
pp. 576-582 ◽  
Author(s):  
Raed Al Dieri ◽  
Flora Peyvandi ◽  
Elena Santagostino ◽  
Muriel Giansily ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Lag Time ◽  
Peak Height ◽  
Factor Vii ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Factor Xi ◽  
Factor Concentration

SummaryWe investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation.Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was somewhat more sensitive to clotting factor decrease than the ETP was.In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time.

scholarly journals FACTOR VII DEFICIENCY IN POLISH HOUND – ACCIDENTAL EVENT OR NEW PERMANENT RISK?

2016 ◽  
Vol 18 (2(66)) ◽  
pp. 227-231
Author(s):  
A. Milczak ◽  
D. Bochyńska ◽  
B. Abramowicz ◽  
M. Staniec ◽  
K. Buczek ◽  
...  
Keyword(s):  
Incidental Finding ◽  
Spontaneous Mutation ◽  
Diagnostic Testing ◽  
Companion Animals ◽  
Screening Tests ◽  
Factor Vii ◽  
Factor Vii Deficiency ◽  
Mixed Breed ◽  
History Of ◽  
Fvii Deficiency

The Polish Hound (ogar polski) is a small, old breed of hunting dogs.The breed was recognized by the Fédération Cynologique Internationale (FCI) in 1966.A three–year–old Polish Hound male, was admitted to the Clinic of Internal Diseases of Companion Animals of Life Science University in Lublin because of signs of haemorhagic diathesis. There was no preceding history of trauma. General clinical examination was unremarkable. On initial diagnostic testing prothrombin time (PT)of the patient was prolonged nearly by three times. To characterize the dog’s coagulopathy further, samples were collected for coagulation screening tests, mixing studies and factor analyses. Investigations revealed factor VII activity below 2%.Unfortunately we had been unable to determine whether the disorder is inherited or is the result of a spontaneous mutation. It is very likely that the nature of described deficit is inherited. Canine hereditary FVII deficiency was first described in 1962 as an incidental finding in Beagles. Later, the defect was identified in another breeds, such as: English Bulldogs, Alaskan Malamutes, Miniature Schnauzers, Boxers, Scottish Deerhounds, Alaskan Klee Kai Dog and mixed–breed dogs. In 2005 a molecular characterization of FVII deficiency in Beagles was described. Unfortunately we had been unable to determine whether the disorder is inherited or is the result of a spontaneous mutation. To our knowledge this case is the first to report of isolated factor VII deficiency in Polish Hound.

Atypical complication in an adult patient with dengue and autoimmune hemolytic anemia: a case report

2021 ◽  
Vol 15 (1) ◽  
pp. 43-48
Author(s):  
Supat Chamnanchanunt ◽  
Pravinwan Thungthong ◽  
Chajchawan Nakhakes ◽  
Putza Chonsawat ◽  
Tawatchai Suwanban
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Rare Complication ◽  
Dengue Infection ◽  
Volume Overload ◽  
Factor Vii ◽  
Severe Dengue ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Recombinant Activated Factor Vii

Abstract Severe dengue infection is associated with life-threatening complications, including severe bleeding. The bleeding tendency is typically associated with the shock phase of infection, for which blood replacement may be needed. However, repetitive blood transfusion can lead to volume overload. Administration of recombinant activated factor VII (rFVIIa) might be used to counteract bleeding without inducing volume overload. We describe the case of a patient with severe dengue infection who presented with intractable bleeding; he was initially treated with massive blood transfusions, which resulted in volume overload. He was then treated with rFVIIa to reverse the bleeding. During the second week of his hospitalization, his hematocrit dropped precipitously, and autoimmune hemolytic anemia was diagnosed. Supportive treatment was provided until recovery. Autoimmune hemolytic anemia is a rare complication in adult patients with dengue. Supportive care was effective for this atypical complication.

scholarly journals Congenital factor VII deficiency in Iraqi children (Single Centre Experience)

2019 ◽  
Vol 36 (2) ◽  
Author(s):  
Ali Ahmed Khudhair ◽  
Afrah Abdul-Mahdi Salih ◽  
Ausama Jamal Kadhum
Keyword(s):  
Clinical Manifestations ◽  
Factor Vii ◽  
Severe Bleeding ◽  
Common Symptom ◽  
Single Centre ◽  
Surgical Interventions ◽  
Factor Vii Deficiency ◽  
Single Centre Experience ◽  
Fvii Deficiency ◽  
Congenital Factor

Background and Objective: Factor VII (FVII) deficiency is probably one of the most common of the rare autosomal recessive coagulation disorders, with an estimated prevalence of l: 500000. All age groups can be affected with FVII deficiency. This study aimed to describe the demographic parameters, symptomatology, hemostatic values and the outcome of FVII deficiency. Methods: This is a retrospective descriptive study of patients with congenital FVII deficiency over a period of seven years from (August 2008 to August 2015). The data were collected by reviewing the files for each patient diagnosed with FVII deficiency. Surgical interventions, complications and follow up visits were recorded. Results: Twenty-four patients were included in this study, 17 females and seven males, below one year was the most common age at presentation. More than half of patients (58.3%) were diagnosed within six months of symptoms onset. The majority of patients had severe phenotype. The most common symptom was epitaxis (41.7%). Five out of 10 patients with FVII level < 1% have either mild to moderate phenotype of the disease without complications; while six out of 14 patients with FVII > 1% had at least one episode of severe bleeding. Three patients had hepatitis C; all were treated by blood products before the introduction of recombinant FVII in Iraq. The outcome of most patients (75%) was normal without complications at time of study. Conclusion: Clinical manifestations of FVII deficiency are variable and they are not necessarily correlated to the FVII level. doi: https://doi.org/10.12669/pjms.36.2.666 How to cite this:Khudhair AA, Salih AAM, Kadhum AJ. Congenital factor VII deficiency in Iraqi children (Single Centre Experience). Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.666 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Identification and Characterization of a New Mutation in Coagulation Factor VII (Carmel mutation), with Different Reactivity Towards Tissue Factors of Different Origin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1396-1396
Author(s):  
Aliza Cassel ◽  
Nurit Rosenberg ◽  
Emad Muhammad ◽  
Rima Dazdik ◽  
Miriam Berl ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Compound Heterozygote ◽  
Factor Vii ◽  
Rabbit Brain ◽  
Molecular Defect ◽  
Bleeding Tendency ◽  
Tissue Factors ◽  
Fvii Deficiency

Abstract Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder manifested by bleeding tendency in homozygotes or compound heterozygotes. The bleeding tendency is variable and does not always correlate with the measured amount of FVII. More than 30 mutations causing FVII deficiency have been identified. The aim of this study was to identify the molecular defect in a family with FVII abnormality and to characterize the functional defect and its clinical consequences. An 80 year old woman showed various prolonged prothrombin time (PT) dependent on the origin of tissue factors (TF) in the reagents, in the range of 5-18%. FVII activity measured using placenta human TF was ~4% and less than 1% using recombinant human TF or rabbit brain TF. Direct sequencing of PCR-amplified FVII genomic DNA exons demonstrated a single homozygous nucleotide exchange G>A in exon 6 predicting missense mutation Tyr164Cys, in close vicinity to the active site of the protease and to the binding site of FX. Sequencing of exon 6 in six members of the family comprising three generations was performed. All of them exhibited low activity of FVII. Direct sequencing of PCR-amplified exon 6 demonstrated that her son, daughter and grand-daughter are heterozygote to the novel mutation, Tyr164Cys, henceforth, Carmel mutation. The grand -daughter (third generation) was identified as a compound heterozygote carrying in addition an Ala244Val mutation along with a Arg353Gln polymorphism, a well-known linkage previously characterized in the Israeli population, inherited from the paternal side. Her FVII activity was 3-7% and 8% FVII antigen. In the individuals heterozygote for Tyr164Cys we detected 41-54% activity and 46-66% antigenic FVII. The measurement of VIIa in the proband and her grand-daughter could not demonstrate any activity in plasma, possibly because of perturbation of the interaction between the mutated FVII and TF or FX which are part of the assay. The heterozygote for Tyr164Cys showed approximately 30% FVIIa of normal controls . Despite the dramatic laboratory presentation, the clinical manifestation of the Tyr164Cys genotype is very mild, suggesting that a low level of FVII is sufficient to prevent bleeding. The homozygous patient reached an old age, gave birth to two children and did not suffer any major bleedings during her life. The compound heterozygote presents a similar phenotype with slightly higher FVII activity and antigen, no measurable FVIIa activity and mild clinical presentation. Further investigation into this novel mutation is needed in order to characterize the interaction of the FVII with TF, phospholipids and FX and to understand the reason for such low amount of FVII protein in plasma. Disclosures No relevant conflicts of interest to declare.

Exclusion of the First EGF Domain of Factor VII by a Splice Site Mutation Causes Lethal Factor VII Deficiency

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 920-926
Author(s):  
John H. McVey ◽  
Emma J. Boswell ◽  
Osamu Takamiya ◽  
Gabriel Tamagnini ◽  
Victor Valente ◽  
...  
Keyword(s):  
Splice Site ◽  
Lethal Factor ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Single Point Mutation ◽  
Severe Bleeding ◽  
Polymorphism Analysis ◽  
Nucleotide Position ◽  
Coagulation Factor Vii ◽  
Fvii Deficiency

We have studied a family with homozygous lethal, blood coagulation factor VII (FVII) deficiency. To identify the mutation responsible for the deficiency, exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by polymerase chain reaction and screened by single-strand conformational polymorphism analysis. The fragment showing aberrant mobility was cloned and sequenced. We detected a single point mutation, a homozygous G to A substitution at nucleotide position 6070, in the invariant GT dinucleotide at the 5′ splice site of intron 4. Homozygosity was confirmed by loss of a site for the restriction endonuclease Mlu I. Analysis of the splicing pattern of ectopic transcripts in lymphocytes in the parents revealed that this mutation is associated with skipping of exon 4, which produces an mRNA encoding FVII with an in-frame deletion of the first epidermal growth factor–like domain (EGF 1). Transient transfection of COS-7 cells with an expression vector containing the ▵EGF 1 FVII cDNA shows that this mutant protein is not expressed. The identification of the molecular basis of the FVII deficiency in this family allowed mutation-specific prenatal diagnosis to be performed in a subsequent pregnancy. In this family complete FVII deficiency is associated with a severe bleeding diathesis but no developmental abnormalities, lending weight to the hypothesis that fetal FVII is not required for the putative angiogenic functions of tissue factor in humans. © 1998 by The American Society of Hematology.

scholarly journals Atypical complication in an adult patient with dengue and autoimmune hemolytic anemia: a case report

2021 ◽  
Vol 15 (1) ◽  
pp. 43-48
Author(s):  
Supat Chamnanchanunt ◽  
Pravinwan Thungthong ◽  
Chajchawan Nakhakes ◽  
Putza Chonsawat ◽  
Tawatchai Suwanban
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Rare Complication ◽  
Dengue Infection ◽  
Volume Overload ◽  
Factor Vii ◽  
Severe Dengue ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Recombinant Activated Factor Vii

Abstract Severe dengue infection is associated with life-threatening complications, including severe bleeding. The bleeding tendency is typically associated with the shock phase of infection, for which blood replacement may be needed. However, repetitive blood transfusion can lead to volume overload. Administration of recombinant activated factor VII (rFVIIa) might be used to counteract bleeding without inducing volume overload. We describe the case of a patient with severe dengue infection who presented with intractable bleeding; he was initially treated with massive blood transfusions, which resulted in volume overload. He was then treated with rFVIIa to reverse the bleeding. During the second week of his hospitalization, his hematocrit dropped precipitously, and autoimmune hemolytic anemia was diagnosed. Supportive treatment was provided until recovery. Autoimmune hemolytic anemia is a rare complication in adult patients with dengue. Supportive care was effective for this atypical complication.

At Disease Presentation, Severity of the Bleeding Symptom Predicts the Following Bleeds in Patients with FVII Deficiency

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 30-30 ◽  
Author(s):  
Matteo ND Di Minno ◽  
Angelika Batorova ◽  
Mariasanta Napolitano ◽  
Alberto Dolce ◽  
Giovanni Di Minno ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Clinical Information ◽  
Factor Vii ◽  
Severe Bleeding ◽  
Clinical Phenotypes ◽  
Treatment Demand ◽  
Bleeding Symptom ◽  
Wide Range ◽  
Fvii Deficiency ◽  
Asymptomatic Individuals

Abstract Abstract 30 Background: Inherited Factor VII (FVII) deficiency is the most common of the “rare” autosomal recessive bleeding disorders. Affected individuals display a wide range of clinical phenotypes and treatment demand may vary from prophylaxis to the need of rare or no replacement at all. As a matter of fact, it would be important to individualize the optimal and safest management with reference to the risk of bleeding. Objective: In a large number of subjects with FVII deficiency, we evaluated whether the type of symptom at disease presentation could help to predict further symptoms during the “Observation Period” (OP). Methods: Appropriate information in subjects with FVII deficiency, collected in the multicentre STER and IF7SG Registries, were employed. OP= time elapsed between the date of disease-presentation symptom and that of enrolment into the registry. Data for this analysis were complete for 687 individuals. Results: At diagnosis, among the 687 subjects (356 [51.8%] females, 331 [48.2%] males, mean age 29.6±19.63 yrs), 272 (39.6%) were asymptomatic; of the symptomatic individuals, 338 (49.2%) displayed a mild “Platelet- Like” (PL) bleeding defect (i.e. muco-cutaneous bleedings) and 77 (11.2%) had a severe, “Hemophilia-Like” (HL), phenotype. Mean age at diagnosis for the asymptomatic individuals was 23.8±18.8; mean ages at disease presentation were 10.54 ±11.8 for the PL, and 5.5 ±12.3 for the HL individuals ( p for trend= 0.000). FVII activity (FVIIc) was: females 17.53±19.68%, males 18.58±17.50% (p=0.460), overall: 18.04 ±18,66%. Of the 338 individuals with a PL-disorder, 268 (79.3%) had new muco-cutaneous bleedings; 51 (15.1%) developed severe bleedings, and 12 (4%) did not develop any subsequent bleed. Among the patients (n=77) with a HL-disorder, 38 (49.4%) experienced new severe bleeds, 34 (44.2%) developed mucosal bleedings, and only 5 (6.5%) had no further bleeds. Among those asymptomatic at diagnosis (n=272), 237 (87.1%) remained asymptomatic, while 35 (12.9%) developed only muco-cutaneous bleedings. Thus, 87.1% of the asymptomatic individual at diagnosis remained so, 79.3% of those with a platelet-like disorder at diagnosis displayed the same type of bleeding and, finally, 50% of those with severe bleedings at diagnosis had, again, severe bleeds. FVIIc helped to refine clinical information. Asymptomatic individuals at diagnosis that subsequently developed muco-cutaneous bleedings, had FVIIc similar to that of individuals with the same mild bleeds at onset (∼15–20%). FVIIc of individuals with PL-disorder at diagnosis who subsequently experienced a life- and limb-threatening bleeding episode, were as low (<5%) as those of individuals that had a severe phenotype at disease presentation. Regardless whether documented at diagnosis or during the OP, severe bleeding was invariably associated with FVIIc <5%. At diagnosis, the latter levels were found in 88.3% of individuals with severe symptoms, in 57.8% of those with muco-cutaneous bleedings and in 14.7% of asymptomatic individuals. Conclusions: In Factor VII deficiency, three clinical phenotypes can be identified: 1. the most prevalent cohort experience muco-cutaneous bleeding (PL-disorder); 2. Ten–15% of patients exhibit potentially life- or limb-threatening hemorrhages, such as hemartroses, central nervous system (CNS) or gastrointestinal (GI), a phenotype that may be as severe or more severe than that in hemophilia, and 3. about 1/3 of cases are asymptomatic and tend to remain so. Bleeding symptom at disease presentation predicts the subsequently developed bleeding phenotype. FVIIc levels refine such clinical prediction and help to identify individuals that call for early prophylaxis or on demand treatment. Disclosures: No relevant conflicts of interest to declare.

Exclusion of the First EGF Domain of Factor VII by a Splice Site Mutation Causes Lethal Factor VII Deficiency

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 920-926 ◽  
Author(s):  
John H. McVey ◽  
Emma J. Boswell ◽  
Osamu Takamiya ◽  
Gabriel Tamagnini ◽  
Victor Valente ◽  
...  
Keyword(s):  
Splice Site ◽  
Lethal Factor ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Single Point Mutation ◽  
Severe Bleeding ◽  
Polymorphism Analysis ◽  
Nucleotide Position ◽  
Coagulation Factor Vii ◽  
Fvii Deficiency

Abstract We have studied a family with homozygous lethal, blood coagulation factor VII (FVII) deficiency. To identify the mutation responsible for the deficiency, exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by polymerase chain reaction and screened by single-strand conformational polymorphism analysis. The fragment showing aberrant mobility was cloned and sequenced. We detected a single point mutation, a homozygous G to A substitution at nucleotide position 6070, in the invariant GT dinucleotide at the 5′ splice site of intron 4. Homozygosity was confirmed by loss of a site for the restriction endonuclease Mlu I. Analysis of the splicing pattern of ectopic transcripts in lymphocytes in the parents revealed that this mutation is associated with skipping of exon 4, which produces an mRNA encoding FVII with an in-frame deletion of the first epidermal growth factor–like domain (EGF 1). Transient transfection of COS-7 cells with an expression vector containing the ▵EGF 1 FVII cDNA shows that this mutant protein is not expressed. The identification of the molecular basis of the FVII deficiency in this family allowed mutation-specific prenatal diagnosis to be performed in a subsequent pregnancy. In this family complete FVII deficiency is associated with a severe bleeding diathesis but no developmental abnormalities, lending weight to the hypothesis that fetal FVII is not required for the putative angiogenic functions of tissue factor in humans. © 1998 by The American Society of Hematology.

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