Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency.

Mariasanta Napolitano, Alessandro Canella, Muriel Giansily-Blaizot, Mirko Pinotti, Guglielmo Mariani, Lara Rizzotto, Rosella Mari, Mario Lapecorella, Alessio Branchini, Francesco Bernardi, Mariasanta Napolitano

Risultato della ricerca: Article

12 Citazioni (Scopus)

Abstract

We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5% and 2.7 ± 0.4% were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7 ± 0.2%) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8 ± 0.9%) and disappeared with rabbit thromboplastin (0.7 ± 0.2%). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400%), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations of the FVII carboxy-terminus resulted in reduced secretion but normal specific activity. These data provide evidence for counteracting pleiotropic effects of the p.R462X mutation, which explains the asymptomatic FVII deficiency, and contributes to our understanding of the role of the highly variable carboxy-terminus of coagulation serine proteases.
Lingua originaleEnglish
pagine (da-a)-
Numero di pagine5
RivistaHaematologica
Volume97
Stato di pubblicazionePublished - 2012

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Factor VII Deficiency
Factor VII
Thromboplastin
Mutation
Factor Xa
Prothrombin Time
Homozygote
Serine Proteases
Rabbits
Antigens

All Science Journal Classification (ASJC) codes

  • Hematology

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Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency. / Napolitano, Mariasanta; Canella, Alessandro; Giansily-Blaizot, Muriel; Pinotti, Mirko; Mariani, Guglielmo; Rizzotto, Lara; Mari, Rosella; Lapecorella, Mario; Branchini, Alessio; Bernardi, Francesco; Napolitano, Mariasanta.

In: Haematologica, Vol. 97, 2012, pag. -.

Risultato della ricerca: Article

Napolitano, M, Canella, A, Giansily-Blaizot, M, Pinotti, M, Mariani, G, Rizzotto, L, Mari, R, Lapecorella, M, Branchini, A, Bernardi, F & Napolitano, M 2012, 'Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency.', Haematologica, vol. 97, pagg. -.
Napolitano, Mariasanta ; Canella, Alessandro ; Giansily-Blaizot, Muriel ; Pinotti, Mirko ; Mariani, Guglielmo ; Rizzotto, Lara ; Mari, Rosella ; Lapecorella, Mario ; Branchini, Alessio ; Bernardi, Francesco ; Napolitano, Mariasanta. / Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency. In: Haematologica. 2012 ; Vol. 97. pagg. -.
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abstract = "We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5{\%} and 2.7 ± 0.4{\%} were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7 ± 0.2{\%}) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8 ± 0.9{\%}) and disappeared with rabbit thromboplastin (0.7 ± 0.2{\%}). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400{\%}), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations of the FVII carboxy-terminus resulted in reduced secretion but normal specific activity. These data provide evidence for counteracting pleiotropic effects of the p.R462X mutation, which explains the asymptomatic FVII deficiency, and contributes to our understanding of the role of the highly variable carboxy-terminus of coagulation serine proteases.",
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T1 - Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency.

AU - Napolitano, Mariasanta

AU - Canella, Alessandro

AU - Giansily-Blaizot, Muriel

AU - Pinotti, Mirko

AU - Mariani, Guglielmo

AU - Rizzotto, Lara

AU - Mari, Rosella

AU - Lapecorella, Mario

AU - Branchini, Alessio

AU - Bernardi, Francesco

AU - Napolitano, Mariasanta

PY - 2012

Y1 - 2012

N2 - We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5% and 2.7 ± 0.4% were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7 ± 0.2%) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8 ± 0.9%) and disappeared with rabbit thromboplastin (0.7 ± 0.2%). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400%), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations of the FVII carboxy-terminus resulted in reduced secretion but normal specific activity. These data provide evidence for counteracting pleiotropic effects of the p.R462X mutation, which explains the asymptomatic FVII deficiency, and contributes to our understanding of the role of the highly variable carboxy-terminus of coagulation serine proteases.

AB - We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5% and 2.7 ± 0.4% were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7 ± 0.2%) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8 ± 0.9%) and disappeared with rabbit thromboplastin (0.7 ± 0.2%). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400%), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations of the FVII carboxy-terminus resulted in reduced secretion but normal specific activity. These data provide evidence for counteracting pleiotropic effects of the p.R462X mutation, which explains the asymptomatic FVII deficiency, and contributes to our understanding of the role of the highly variable carboxy-terminus of coagulation serine proteases.

KW - FACTOR VII DEFICIENCY, MOLECULAR VARIANTS

UR - http://hdl.handle.net/10447/71163

M3 - Article

VL - 97

SP - -

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -