Abstract
Severe inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder with a poor relationship between FVII coagulant activity and bleeding tendency. Both clinical expression and mutational spectrum are highly variable. We have screened for mutations the FVII gene of 37 unrelated patients with a FVII coagulant activity less than 5% of normal pooled plasmas. The nine exons with boundaries and the 5′ flanking region of the FVII gene were explored using a combination of denaturing gradient gel electrophoresis and direct DNA sequencing. This strategy allowed us to characterise 68 out of the 74 predicted FVII mutated alleles. They corresponded to a large panel of 40 different mutations. Among these, 18 were not already reported. Genotypes of the severely affected patients comprised, on both alleles, deleterious mutations which appeared to be related to a total absence of activated FVII. We suggest that this absence of functional FVII can explain the severe clinical expression. Whether a small release of FVII is sufficient to initiate the coagulation cascade and to prevent the expression of a severe phenotype, requires further investigations.
Similar content being viewed by others
Article PDF
References
Cooper DN, Millar DS, Wacey A, Banner DW, Tuddenham EGD: . Inherited factor VII deficiency: molecular genetics and pathophysiology. Thromb Haemost 1997 78: 151–160.
Triplett DA, Brandt JT, McGann Batard MA, Schaeffer Dixon JL, Fair DS: . Hereditary Factor VII deficiency: heterogeneity defined by combined functional and immunochemical analysis. Blood 1985 66: 1284–1287.
Peyvandi F, Mannucci PM, Asti D, Abdoullahi M, Di Rocco N, Sharifian R: . Clinical manifestations in 28 Italian and Iranian patients with severe factor VII deficiency. Haemophilia 1997 3: 242–246.
Wulff K, Herrmann FH: . Twenty two novel mutations of factor VII gene in Factor VII deficiency. Hum Mutat 2000 15: 489–496.
Arbini AA, Bodkin D, Lopaciuk S, Bauer KA: . Molecular analysis of Polish patients with factor VII deficiency. Blood 1994 84: 2214–2220.
Peyvandi F, Jenkins PV, Mannucci PM et al:. Molecular characterisation and three-dimensional structural analysis of mutations in 21 unrelated families with inherited factor VII deficiency. Thromb Haemost 2000 84: 250–257.
O'Hara PJ, Grant FJ, Haldeman BA et al:. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci USA 1987 84: 5158–5162.
Abrams ES, Murdaugh SE, Lerman LS: . Comprehensive detection of single base changes in human genomic DNA using denaturing gradient gel electrophoresis and a GC clamp. Genomics 1990 7: 463–475.
Biron C, Lamarti H, Schved JF et al:. Diagnosis strategies in activated protein C resistance: is genotyping still necessary? Clin Lab Haem 1997 19: 67–71.
Marchetti G, Ferrati M, Patracchini P, Redaelli R, Bernardi F: . A missense mutation (178Cys→Tyr) and two neutral dimorphisms (115His and 333Ser) in the human coagulation factor VII gene. Hum Mol Gen 1993 2: 1055–1056.
Marchetti G, Patracchini P, Gemmati D et al:. Detection of two missense mutations and characterization of a repeat polymorphism in the factor VII gene (F7). Hum Genet 1992 89: 497–502.
Green F, Kelleher C, Wilkes H, Temple A, Meade TW, Humphries S: . A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb Vasc Biol 1991 11: 540–546.
Peyvandi F, Mannucci PM, Bucciarelli P et al:. A novel polymorphism in intron 1a of the human factor VII gene (G73A): study of a healthy Italian population and of 190 young survivors of myocardial infarction. Br J Haematol 2000 108: 247–253.
Bernardi F, Castaman G, Redaelli R et al:. Topologically equivalent mutations causing dysfunctional coagulation factors VII (294 Ala→Val) and X (334 Ser→Pro). Hum Mol Gen 1994 3: 1175–1177.
Fagan K, Wilkinson I, Allen M, Brownlea S: . The coagulation factor VII regulator is located on 8p23.1. Hum Genet 1988 79: 365–367.
Mariani G, Lo Coco L, Bernardi F, Pinotti M: . Molecular and clinical aspects of factor VII deficiency. Blood Coagul Fibrinolysis 1998 9: S83–S88.
McVey JH, Boswell EJ, Takamiya O et al:. Exclusion of the first EGF domain of factor VII by a splice site mutation causes lethal factor VII deficiency. Blood 1998 92: 920–926.
Arbini AA, Pollak ES, Bayleran JK, High KA, Bauer KA: . Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in factor VII promoter. Blood 1997 89: 176–172.
Rosen ED, Chan JCY, Idusogie E et al:. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997 390: 290–293.
Chaing S, Clarke B, Sridhara S et al:. Severe factor VII deficiency caused by mutations abolishing the cleavage site for activation and altering binding to tissue factor. Blood 1994 83: 3524–3535.
Bharadwaj D, Lino M, Kontoyianni M, Smith KJ, Foster DC, Kisiel W: . Factor VII central. J Biol Chem 1996 271: 30685–30691.
Higashi S, Matsumoto N, Iwanaga S: . Molecular mechanism of tissue factor-mediated acceleration of factor VIIa activity. J Biol Chem 1996 271: 26569–26574.
Arbini AA, Mannucci PM, Bauer KA: . A Thr 359 Met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule. Blood 1996 87: 5085–5094.
Katsumi A, Matsushita T, Yamazaki T, Sugiura I, Kojima T, Saito H: . Severe Factor VII deficiency caused by a novel mutation His348 to Gln in the catalytic domain. Thromb Haemost 2000 83: 239–243.
Hunault M, Arbini AA, Carew JA, Peyvandi F, Bauer KA: . Characterization of two naturally occuring mutations in the second epidermal growth factor-like domain of factor VII. Blood 1999 93: 1237–1244.
Leonard BJN, Chen Q, Blajchman MA et al:. Factor VII deficiency caused by a structural variant N57D of the first epidermal growth factor domain. Blood 1998 91: 142–148.
Shapiro MB, Senapathy P: . RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 1987 15: 7155–7174.
Pinotti M, Toso R, Redaelli R, Berrettini M, Marchetti G, Bernardi F: . Molecular mechanisms of FVII deficiency: expression of mutations clustered in the IVS7 donor splice site of factor VII gene. Blood 1998 92: 1646–1651.
Pollak ES, Hung HL, Godin W, Overton GC, High KA: . Functional characterization of the human factor VII 5′-flanking region. J Biol Chem 1996 271: 1738–1747.
Carew JA, Lopaciuk S, Bauer A: . A new promoter mutation in the HNF4 binding region of factor VII gene in a patient with severe factor VII deficiency. Thromb Haemost 1999 suppl: 17 (abstr).
Ghanem N, Costes B, Martin J et al:. Twenty four novel hemophilia B mutations revealed by rapid scanning of the whole factor IX gene in a French population sample. Eur J Hum Genet 1993 1: 144–155.
Acknowledgements
The authors are grateful to Pr Thierry Maudelonde and Dr Jean-Marc Rey for technical help in sequence analysis. The authors wish to also acknowledge Dr Mike Morris and Pr Philippe de Moerloose for review of the manuscript. This work was supported by the programme Hospitalier de Recherche Clinique 1997, CHU Montpellier.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
Giansily-Blaizot, M., Aguilar-Martinez, P., Biron-Andreani, C. et al. Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency. Eur J Hum Genet 9, 105–112 (2001). https://doi.org/10.1038/sj.ejhg.5200593
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200593
Keywords
This article is cited by
-
Factor X M402T: a homozygous missense mutation identified as the cause of cross-reacting material-reduced deficiency
International Journal of Hematology (2014)
-
Identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia
Diagnostic Pathology (2012)
-
Congenital FVII deficiency and thrombotic events after replacement therapy
Journal of Thrombosis and Thrombolysis (2011)