Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency

Rebecca E. Saunders; Nuha Shiltagh; Keith Gomez; Gillian Mellars; Carolyn Cooper; David J. Perry; Edward G. Tuddenham; Stephen J. Perkins

doi:10.1160/TH09-01-0044

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2009; 102(02): 287-301
DOI: 10.1160/TH09-01-0044

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency

Rebecca E. Saunders

¹Institute of Structural and Molecular Biology, University College London, London, UK

,

Nuha Shiltagh

¹Institute of Structural and Molecular Biology, University College London, London, UK

,

Keith Gomez

²Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond Street, London, UK

,

Gillian Mellars

²Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond Street, London, UK

,

Carolyn Cooper

³Department of Haematology, Addenbrookes Hospital, Hills Road, Cambridge, UK

,

David J. Perry

³Department of Haematology, Addenbrookes Hospital, Hills Road, Cambridge, UK

,

Edward G. Tuddenham

²Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond Street, London, UK

,

Stephen J. Perkins

¹Institute of Structural and Molecular Biology, University College London, London, UK

› Institutsangaben

Abstract

Summary

Factor XI (FXI) functions in blood coagulation. FXI is composed of four apple (Ap) domains and a serine protease (SP) domain. Deficiency of FXI leads to an injury-related bleeding disorder, which is remarkable for the lack of correlation between bleeding symptoms and FXI coagulant activity (FXI:C).The number of mutations previously reported in our interactive web database (http://www.FactorXI.org) is now significantly increased to 183 through our new patient studies and from literature surveys. Eight novel missense mutations give a total of 120 throughout the FXI gene (F11).The most abundant defects in FXI are revealed to be those from low-protein plasma levels (Type I: CRM-) that originate from protein misfolding, rather than from functional defects (Type II: CRM+). A total of 70 Ap missense mutations were analysed using a consensus Ap domain structure generated from the FXI dimer crystal structure. This showed that all parts of the Ap domain were affected.The 47 SP missense mutations were also distributed throughout the SP domain structure.The periphery of the Ap β-sheet structure is sensitive to structural perturbation caused by residue changes throughout the Ap domain, yet this β-sheet is crucial for FXI dimer formation. Residues located at the Ap4:Ap4 interface in the dimer are much less directly involved. We conclude that the abundance of Type I defects in FXI results from the sensitivity of the Ap domain folding to residue changes within this, and discuss how structural knowledge of the mutations improves our understanding of FXI deficiencies.

Keywords

Factor XI - coagulation - mutations - web database

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Referenzen

References
1 Asakai R, Davie EW, Chung DW. Organization of the gene for human factor XI. Biochemistry 1987; 26: 7221-7228.
2 Fujikawa K, Chung DW, Hendrickson LE. et al. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 1986; 25: 2417-2424.
3 Brown PJ, Gill AC, Nugent PG. et al. Domains of invasion organelle proteins from apicomplexan parasites are homologous with the Apple domains of blood coagulation factor XI and plasma pre-kallikrein and are members of the PAN module superfamily. FEBS Lett 2001; 497: 31-38.
4 McMullen BA, Fujikawa K, Davie EW. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry 1991; 30: 2056-2060.
5 Dorfman R, Walsh PN. Noncovalent interactions of the Apple 4 domain that mediate coagulation factor XI homodimerization. J Biol Chem 2001; 276: 6429-6438.
6 Cheng Q, Sun MF, Kravtsov DV. et al. Factor XI apple domains and protein dimerization. J Thromb Haemost 2003; 01: 2340-2347.
7 Shpilberg O, Peretz H, Zivelin A. et al. One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 1995; 85: 429-432.
8 Bolton-Maggs PH, Patterson DA, Wensley RT. et al. Definition of the bleeding tendency in FXI-deficient kindred: a clinical and laboratory study. Thromb Haemost 1995; 73: 194-202.
9 Asakai R, Chung DW, Ratnoff OD. et al. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci USA 1989; 86: 7667-7671.
10 Peretz H, Zivelin A, Usher S. et al. A 14-bp deletion (codon 554 del AAGgtaacagagtg) at exon 14/intron N junction of the coagulation factor XI gene disrupts splicing and causes severe factor XI deficiency. Hum Mutat 1996; 08: 77-78.
11 Peretz H, Mulai A, Usher S. et al. The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin. Blood 1997; 90: 2654-2659.
12 Zivelin A, Bauduer F, Ducout L. et al. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood 2002; 99: 2448-2454.
13 Bolton-Maggs PH, Peretz H, Butler R. et al. A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2004; 02: 918-924.
14 Quélin F, Trossaërt M, Sigaud M. et al. Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation. J Thromb Haemost 2004; 02: 71-76.
15 Saunders RE, O’Connell NM, Lee CA. et al. Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools. Hum Mutat 2005; 26: 192-198.
16 O’Connell NM, Saunders RE, Lee CA. et al. Structural interpretation of 42 mutations causing factor XI deficiency using homology modelling. J Thromb Haemost 2005; 03: 127-138.
17 Jin L, Pandey P, Babine RE. et al. Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions. J Biol Chem 2005; 280: 4704-4712.
18 Papagrigoriou E, McEwan PA, Walsh PN. et al. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 2006; 13: 557-558.
19 Samuel D, Cheng H, Riley PW. et al. Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation. Proc Natl Acad Sci USA 2007; 104: 15693-15698.
20 Navaneetham D, Jin L, Pandey P. et al. Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem 2005; 280: 36165-36175.
21 Orengo CA, Taylor WR. SSAP: sequential structure alignment program for protein structure comparison. Methods Enzymol 1996; 266: 617-635.
22 Kabsch W, Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983; 22: 2577-2637.
23 Perkins SJ, Smith KF. Identity of the putative serine protease fold in proteins of the complement system with nine relevant crystal structures. Biochem J 1993; 295: 109-114.
24 Mitchell M, Cutler J, Thompson S. et al. Heterozygous factor XI deficiency associated with three novel mutations. Br J Haematol 1999; 107: 763-765.
25 de Raucourt E, de Mazancourt P, Quélin F. Four novel FXI gene mutations in three factor XIdeficient patients. Blood Coagul Fibrinolysis 2008; 19: 240-242.
26 Hill M, McLeod F, Franks H. et al. Genetic analysis in FXI deficiency: six novel mutations and the use of a polymerase chain reaction-based test to define a whole gene deletion. Br J Haematol 2005; 129: 825-829.
27 Meijers JC, Davie EW, Chung DW. Expression of human blood coagulation factor XI: characterization of the defect in factor XI type III deficiency. Blood 1992; 79: 1435-1440.
28 Guella I, Solda G, Spena S. et al. Molecular characterization of two novel mutations causing factor XI deficiency: A splicing defect and a missense mutation responsible for a CRM+ defect. Thromb Haemost 2008; 99: 523-530.
29 Ventura C, Santos AI, Tavares A. et al. Molecular genetic analysis of factor XI deficiency: identification of five novel gene alterations and the origin of type II mutation in Portuguese families. Thromb Haemost 2000; 84: 833-840.
30 Mitchell MJ, Dai L, Clarke JB. et al. Characterisation of five factor XI mutations. Thromb Haemost 2007; 97: 884-889.
31 Kravtsov DV, Monahan PE, Gailani D. A classification system for cross-reactive material-negative factor XI deficiency. Blood 2005; 105: 4671-4673.
32 Kravtsov DV, Wu W, Meijers JC. et al. Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. Blood 2004; 104: 128-314.
33 Quelin F, Frère C, Pouymayou C. et al. Prospective analysis of factor XI deficiencies in the Marseilles identified four novel mutations among 12 consecutive unrelated families. Blood Coag Fibrin 2009; 20: 84-88.
34 Saunders RE, Abarrategui-Garrido C, Frémeaux-Bacchi V. et al. The interactive Factor H – atypical Haemolytic Uraemic Syndrome mutation database and website: Update and integration of Membrane Cofactor Protein and Factor I mutations with structural models. Human Mutation 2007; 28: 222-234.
35 Baglia FA, Jameson BA, Walsh PN. Identification and chemical synthesis of a substrate-binding site for factor IX on coagulation factor XIa. J Biol Chem 1991; 266: 24190-24197.
36 Baglia FA, Jameson BA, Walsh PN. Identification and characterization of a binding site for factor XIIa in the Apple 4 domain of coagulation factor XI. J Biol Chem 1993; 268: 3838-3844.
37 Baglia FA, Jameson BA, Walsh PN. Identification and characterization of a binding site for platelets in the Apple 3 domain of coagulation factor XI. J Biol Chem 1995; 270: 6734-6740.
38 Baglia FA, Walsh PN. A binding site for thrombin in the apple 1 domain of factor XI. J Biol Chem 1996; 271: 3652-3658.
39 Tress M, Ezkurdia I, Grana O. et al. Assessment of predictions submitted for the CASP6 comparative modeling category. Proteins 2005; 07: 27-45.
40 Orengo CA, Jones DT, Thornton JM. Bioinformatics: Sequence, Structure, Function. BIOS Scientific Publishers; 2003. Abingdon, UK.:
41 Meijers JC, McMullen BA, Bouma BN. The contact activation proteins: a structure/function overview. Agents Actions Suppl 1992; 38: 219-230.
42 Riley PW, Cheng H, Samuel D. et al. Dimer dissociation and unfolding mechanism of coagulation factor XI Apple 4 domain: Spectroscopic and mutational analysis. J Mol Biol 2007; 367: 558-573.
43 Friedrich R, Panizzi P, Fuentes-Prior P. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 2003; 425: 535-539.
44 Schmidt A, Ogawa T, Gailani D. et al. Structural role of Gly193 in serine proteases: Investigations of a Gly555Glu (Gly193 in chymotrypsin) mutant of blood coagulation factor XI. J Biol Chem 2004; 279: 29485-29492.
45 James HL, Girolami A, Fair DS. Molecular defect in coagulation factor XFriuli results from a substitution of serine for proline at position 343. Blood 1991; 77: 317-323.
46 Wulff K, Herrmann FH. Twenty two novel mutations of the factor VII gene in factor VII deficiency. Hum Mutat 2000; 15: 489-496.
47 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.
48 Gailani D, Schmidt A, Sun MF. et al. A cross-reactive material positive variant of coagulation factor XI (FXIP520L) with a catalytic defect. J Thromb Haemost 2007; 05: 781-787.
49 Sun MF, Baglia FA, Ho D. et al. Defective binding of factor XI-N248 to activated human platelets. Blood 2001; 98: 125-129.
50 Wu W, Sinha D, Shikov S. et al. Factor XI homodimer is essential for normal proteolytic activation by Factor XIIa, thrombin and Factor XIa. J Biol Chem 2008; 283: 18655-18664.
51 Smith SB, Verhamme IM, Sun MF. et al. Characterization of novel forms of coagulation factor XIa: Independence of factor XIa subunits in factor IX activation. J Biol Chem 2008; 283: 6696-6705.
52 Martincic D, Zimmerman SA, Ware RE. et al. Identification of mutations and polymorphisms in the factor XI genes of an African American family by dideoxyfingerprinting. Blood 1998; 92: 3309-3317.
53 Mitchell M, Harrington P, Cutler J. et al. Eighteen unrelated patients with factor XI deficiency, four novel mutations and a 100% detection rate by denaturing high-performance liquid chromatography. Br J Haematol 2003; 121: 500-502.
54 Alhaq A, Leach ME, Pepper D. et al. Novel mutations in heterozygous factor XI deficiency and hemorrhagic tendency. Blood 2000; 96: 80b.