Identification of a new haemophilia B<sub>M</sub> case produced by a mutation located at the carboxy terminal cleavage site of activation peptide

Solera, Jesús; Magallón, M.; Martin‐Villar, J.; Coloma, Antonio

doi:10.1111/j.1365-2141.1991.tb04452.x

Cited by 4 publications

(2 citation statements)

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“… 9 Seminal studies have indicated that single cleavage at R191 does not produce catalytic activity but converts FIX zymogen into a factor VIII (FVIII)‐binding enzyme, 10 , 11 whereas single cleavage at R226 develops catalytic activity but results in suboptimal binding to the FVIII light chain. 11 , 12 Accordingly, missense mutations at these positions are associated in HB patients with moderate/mild (R191) 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 or severe (R226, HB m mutation subclass) 14 , 22 , 23 , 24 , 25 , 26 , 27 , 28 FIX deficiency. Failure in the production of activated FIX (FIXa) 14 , 24 , 29 has been modelled in HB mice (R226W).…”

Section: Introductionmentioning

confidence: 99%

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

Branchini

Morfini

Lunghi

et al. 2022

Journal of Thrombosis and Haemostasis

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Section: Introductionmentioning

confidence: 99%

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

Branchini

Morfini

Lunghi

et al. 2022

Journal of Thrombosis and Haemostasis

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“…In most cases, the mutated residue corresponds to the P1 site (i.e. the C-terminal residue of the activation peptide) [27][28][29][30][31][32][33]. However, some mutations involving the P1¢ and P2¢ positions (i.e.…”

Section: Discussionmentioning

confidence: 99%

A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

Bozzao¹,

Rimoldi²,

Asselta³

et al. 2007

The FEBS Journal

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Coagulation factor XI (FXI) is the precursor of a trypsin-like serine protease that catalyzes, upon activation, the conversion of factor IX (FIX) to activated FIX (FIXa) [1,2]. Human FXI, primarily produced by hepatocytes, is a glycoprotein of 160 kDa circulating in plasma in a noncovalent complex with high molecular mass kininogen [3]. Structurally, FXI zymogen comprises four N-terminal tandem repeats of about 90 residues, named apple domains (Ap1-4), followed by a catalytic serine protease domain located at the C-terminal end. Uniquely among coagulation serine proteases, FXI is secreted as a homodimer composed of two identical polypeptide chains linked by noncovalent interactions and by a Cys321-Cys321 disulfide bond between the Ap4 domains [4,5].Among serine proteases that can activate FXI, i.e. activated factor XII (FXIIa), FXIa, and thrombin, the main physiologic activator is actually thrombin formed on the surface of activated platelets [6][7][8]. Cleavage at the Arg369-Ile370 bond in each monomer produces both an N-terminal heavy chain, which binds FIX and high molecular mass kininogen [9], and a C-terminal Coagulation factor XI (FXI) is the zymogen of a serine protease that, when converted to its active form, contributes to blood coagulation through proteolytic activation of factor IX. FXI deficiency is typically an autosomal recessive disorder, characterized by bleeding symptoms mainly associated with injury or surgery. Of the more than 100 FXI gene mutations reported in FXI-deficient patients, most are associated with a proportional decrease in FXI functional and immunologic levels (type I defects), whereas only a few mutations leading to the presence of dysfunctional molecules in plasma have been molecularly analyzed to date (type II deficiencies). We report the functional and molecular characterization of a missense mutation (Val371Ile) identified, in the heterozygous state, in a 25-year-old Italian male with mild FXI deficiency. Laboratory analysis revealed reduced functional FXI levels (34%), but normal antigen levels (102%), distinctive of a type II defect. Given the proximity of Val371 to the FXI activation site, a possible interference with zymogen activation was postulated. Expression experiments of the FXI-Val371Ile recombinant protein, followed by activation assays, showed both a different time course in FXI activation and a slight delay in factor IX activation by thrombinactivated FXI.

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Haemophilia B: database of point mutations and short additions and deletions--third edition, 1992

Giannelli¹,

Green²,

High

et al. 1992

Nucleic Acids Research

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The data base below lists known point mutations and short deletions and additions in the factor IX gene, causing the bleeding disorder haemophilia B or Christmas disease (for reviews, see Brownlee 1988, Giannelli 1989, Thompson 1990, Green et al 1991a These mutations result in a defective clotting factor IX-a glycoprotein of 415 amino acid residues normally present in plasma and an essential component of the clotting cascade. The disease is an X-linked inherited recessive disorder affecting 1 in about 30,000 males and only very rarely females.The purpose of this database is to update last year's one (Giannelli et al, 1991) by collecting in an accessible, summary form, molecular data on the causative mutations of haemophilia B patients worldwide. It is not intended to replace primary publications although it does contain a significant amount of unpublished work. As in previous years, we have included r observations of the same mutation, as well as molecularly unique mutations. We have continued our database numbering system (Giannelli et al (1991) giving all patients a unique Patient Identity Number (PIN or ID number).The factor IX gene lies on the long arm of the x chromosome at Xq27 and its entire sequence of 33 kb is known (Yoshitake et al, 1985). It contains 8 exons (a-h) encoding 6 major domains of factor IX. These are: (1) exon a-a hydrophobic signal peptide which targets the protein for secretion from the hepatocyte into the blood stream. (2) exons b and c-a propeptide and gla domain,-the latter containing 12 -y-carboxyglutamyl residues. This post-translational modification is required for the correct folding and calcium binding of factor IX. (3) exon d-a type B, or first epidermal growth factor-like domain, which shows homology to epidermal growth factor (EGF) and, in addition, contains conserved carboxylate residues including a ,hydroxyaspartate at amino acid 64. This domain binds an additional Ca2+ with high affinity (Handford et al, 1991). ( 4) exon e-a type A, or second epidermal growthfactor-like (EGF) domain which lacks the conserved carboxylate residues of the EGF type B domain. (5) exon f-an activation domain, within which factor XIa cleaves twice, converting factor IX to IXa; (6) exons g and h-the serine protease or catalytic domain, responsible for the proteolysis of factorxto Xa. This region is homologous to other well studied serine proteases (e.g. chymotrypsin) and it is thought likely that his (221), asp (269) and ser (365), all participate in the classical catalytic mechanism.Factor IX is initially synthesised in the liver as a precursor molecule, either 46, 41 or 39 amino acids (it is not known which, although 39 is probable (Pang et al, 1990)) longer at its Nterminus than the 415-long mature factor IX found in plasma. Processing steps occur in the hepatocyte prior to secretion and sequentially remove the hydrophobic signal peptide and the propeptide. In addition to the -y-carboxylation of the 12 N-terminal glutamyl residues carried out by a vitamin K-dependent carboxylase, and the parti...

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Identification of a new haemophilia B_M case produced by a mutation located at the carboxy terminal cleavage site of activation peptide

Cited by 4 publications

References 20 publications

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

Haemophilia B: database of point mutations and short additions and deletions--third edition, 1992

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Identification of a new haemophilia BM case produced by a mutation located at the carboxy terminal cleavage site of activation peptide

Cited by 4 publications

References 20 publications

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes

A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

Haemophilia B: database of point mutations and short additions and deletions--third edition, 1992

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Identification of a new haemophilia B_M case produced by a mutation located at the carboxy terminal cleavage site of activation peptide