F XI Deficiency Mutation Database©
Full List of Mutations
c.-54G>A -
Nucleotide: c.-54G>A Mutation Type: Promoter Region
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: (Mitchell et al., 2006)
Patient Info: +
c.-2+120G>A -
Nucleotide: c.-2+120G>A Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Quelin et al 2004).
c.-1-403G>T -
Nucleotide: c.-1-403G>T Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: (Tarumi et al 2003).
c.-1-273C>G -
Nucleotide: c.-1-273C>G Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: (Tarumi et al 2003).
c.-1-231T>C -
Nucleotide: c.-1-231T>C Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Peretz et al 1997). (Quelin et al 2004).
c.-1-198T>G -
Nucleotide: c.-1-198T>G Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Quelin et al 2004).
c.-1-138C>A -
Nucleotide: c.-1-138C>A Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Ventura et al 2000). (Quelin et al 2004).
Met-18Ile  (1) -
Nucleotide: c.3G>T Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: Ref Type: Full
Comments: Mutations affecting the ATG initiation codon have not been widely reported, and the loss of the initiation methionine in the Met-18Ile variant was expected to be severely detrimental to protein synthesis and secretion. Expression studies show that no FXI is secreted, but surprisingly apparently normal (160 kDa) dimeric FXI was detected by western blot from cell lysates. (Mitchell MJ et al 2007)
Patient Info: +
Tyr-14Stop  (5) -
Nucleotide: c.15T>A Mutation Type: Nonsense
Domain: Signal Peptide Phenotype: U
Position: Ref Type: Abstract
Comments: (Neerman-Arbez et al 2007)
Patient Info: +
Ser-4Leu  (15) -
Nucleotide: c.44C>T Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: Ref Type: Full
Comments: (Quelin et al, 2006)
Patient Info: +
Gly-1Arg  (18) CV
Nucleotide: c.52G>C Mutation Type: Missense
Domain: Signal Peptide Phenotype: I
Position: Ref Type: Full
Comments: Signal peptide prediction analysis results showed that this mutation would disrupt the original signal peptide cutting site between -1 and +1 amino acid position, resulting in impaired secretion of the synthesised FXI protein (Wang J et al 2009).
0  (19) CVT
Nucleotide: Mutation Type:
Domain: Apple 1 Phenotype: U
Position: Ref Type: Full
Comments:
c.56-1209dupCA CVT
Nucleotide: c.56-1209dupCA Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Bodfish et al 1991). (Peretz et al 1997).
Glu1Stop  (19) CVTQ
Nucleotide: c.55G>T Mutation Type: Nonsense
Domain: Introgenic Region Phenotype: I
Position: Ref Type: Full
Comments: (Mitchell et al., 2006)
Patient Info: +
c.55+6T>G, +10insAG CVTQL
Nucleotide: c.55+6T>G, +10insAG Mutation Type: Splice Site
Domain: Apple 1 Phenotype: I
Position: - Ref Type: Full
Comments: (Castaman G 2008)
Patient Info: +
Gln5Stop  (23) CVTQLLKD
Nucleotide: c.67C>T Mutation Type: Nonsense
Domain: Apple 1 Phenotype: U
Position: S (C1-βA Loop) Ref Type: Abstract
Comments: Castaman G et al 2007 (ISTH Poster Abstract)
c.73-86del VTQLLKDTC
Nucleotide: c.73-86del Mutation Type: Deletion
Domain: Apple 1 Phenotype: I
Position: - Ref Type: Full
Comments: 14bp deletion in exon 3 - includes codons 7-11 and leads to a frameshift creating a premature stop at codon 13 (Zucker M et al 2007).
Patient Info: +
78-80delGGA CFEGGDITT
Nucleotide: 78-80delGGA Mutation Type: Deletion
Domain: Apple 1 Phenotype: I
Position: - Ref Type: Full
Comments: The trinucleotide deletion predicts both the substitution of Lysine at codon 8 with Asparagine and the deletion of the subsequent Aspartate (Lys8Asn/delAsp9). Lys8 and Asp9 are located in exposed loops of Ap1 shaping the intricate curved antiparallel beta-sheet characteristic of the Ap domains. Lys8 and Asp9 are not involved in intra-molecule salt bridges and therefore could be available for protein-protein interactions. Mutation of Lys8 to an Asn residue and deltion of Asp9 is predicted to drastically change the architecture and electrostatic surface of the nearby region: the surface aquires an hydrophobic nature, while the beta-sheet loses the second and fifth strands. Expression studies on this mutant reveals a secretion defect and the mutant does not accumulate intracellularly suggesting an efficient degradation of retained misfolded proteins(Spena S et al 2009).
Patient Info: +
Asp16His  (34) FEGGDITTV
Nucleotide: c.100G>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: E (βC) Ref Type: Full
Comments: Amount of mutant protein secreted from cells in vitro is reduced. The replacement of Asp 16 in the first apple domain of factor XI is a radical substitution, because the wild-type aspartate side chain is small and negatively charged at physiologic pH, whereas the histidine group is bulky and hydrophobic with neutral charge - the alteration of charge and shape and the resultant conformational change of this region of the molecule might interfere with chain folding. (Pugh et al 1995).
Val20Ala  (38) DITTVFTPS
Nucleotide: c.113T>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: E (βC) Ref Type: Abstract
Comments: Found in heterozygous patient (Zivelin et al., 1999 Abstract 2). Substitution of FXI-Val20 by Ala in BHK cells caused profoundly decreased FXI secretion (22% of wild-type by cells) despite the presence of only slightly reduced amounts of FXI dimer within the cells (Zucker M et al 2007).
Patient Info: +
Pro23Leu  (41) TVFTPSAKY
Nucleotide: c.122C>T Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: S (βC-α-helix Loo) Ref Type: Full
Comments: (Quelin et al., 2005).
Patient Info: +
Pro23Gln  (41) TVFTPSAKY
Nucleotide: c.122C>A Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: S (βC-α-helix Loo) Ref Type: Full
Comments: (Mitchell et al., 2006})
Patient Info: +
Ser24Arg  (42) VFTPSAKYC
Nucleotide: c.126C>G Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: S (βC-α-helix Loo) Ref Type: Full
Comments: Ser24Arg lies at the start of α-helix A1 within the Ap1 domain. In the crystal structure, this sidechain points towards the interdomain contacts with the Ap2 domain and the replacement with a larger charged residue is predicted to affect the protein structure (Saunders RE et al 2009).
Patient Info: +
Cys28Phe  (46) SAKYCQVVC
Nucleotide: c.137G>T Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: This mutation represents a structurally significant change as it abolishes a Cys28–Cys58 disulphide bridge that is essential for the folding of the first apple domain. Expression studies of similar C38R variant in the A1 domain (Zivelin et al 2002) have demonstrated that, although intracellular production was normal, this variant was not secreted, probably because of abnormal folding. A similar mechanism of action could therefore be proposed for C28F (Hill et al 2005)
Patient Info: +
Gln29His  (47) AKYCQVVCT
Nucleotide: c.141G>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: Mutant protein was not secreted by transfected HEK293 cells (Bolton-Maggs et al 2003 Abstract).
Patient Info: +
Thr33Pro  (51) QVVCTYHPR
Nucleotide: c.151A>C Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: H (α-helix) Ref Type: Full
Comments: Thr33Pro and Thr33Ile. These changes convert hydrophilic and moderately sized threonine to hydrophobic, large proline and isoleucine, respectively. Thr33 lies in the first a-helix, in a buried region of Apple 1 domain and just next to a cysteine residue which forms the disulphide bond. On the other hand, the threonine residue is conserved in positions 33, 123, 213 and 304 of four Apple domains, in the same position relative to the a-helix of each domain. Therefore, it seems that this amino acid is essential for proper function of the protein and its alteration is not conservative (Fard-Esfahani P et al 2008).
Thr33Ile  (51) QVVCTYHPR
Nucleotide: c.152C>T Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: H (α-helix) Ref Type: Full
Comments: Thr33Pro and Thr33Ile. These changes convert hydrophilic and moderately sized threonine to hydrophobic, large proline and isoleucine, respectively. Thr33 lies in the first a-helix, in a buried region of Apple 1 domain and just next to a cysteine residue which forms the disulphide bond. On the other hand, the threonine residue is conserved in positions 33, 123, 213 and 304 of four Apple domains, in the same position relative to the a-helix of each domain. Therefore, it seems that this amino acid is essential for proper function of the protein and its alteration is not conservative (Fard-Esfahani P et al 2008).
Tyr35His  (53) VCTYHPRCL
Nucleotide: c.157C>T Mutation Type: Polymorphism
Domain: Apple 1 Phenotype: U
Position: S (α-helix-βD Loo) Ref Type: None
Comments: dbSNP ID: rs55956266 Tyr35His is surface exposed in the FXI monomer and is not predicted to cause structural perturbations (Saunders RE et al 2009).
Cys38Arg  (56) YHPRCLLFT
Nucleotide: c.166T>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: C (α-helix-βD Loo) Ref Type: Full
Comments: High prevalence in French Basque population. Mutant protein synthesized in BHK transfected cells but not secreted. (Zivelin et al 2002).
Patient Info: +
Cys38Trp  (56) YHPRCLLFT
Nucleotide: c.168T>G Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: C (α-helix-βD Loo) Ref Type: Full
Comments: Cys38 is a buried residue located in a random coil of Ap1 and is involved in the Cys32-Cys38 disulphide bridge. This disulphide bridge represents one of three conserved bridges that are responsible for the correct folding of the Ap domains. Therefore, Cys38Trp mutation is likely to significantly impair folding of the Ap1 domain. Expression studies reveal a secretion defect (Spena S et al 2009) (Castaman G et al 2005 ISTH Poster Abstract)
Patient Info: +
Cys38Stop  (56) YHPRCLLFT
Nucleotide: c.168T>A Mutation Type: Nonsense
Domain: Apple 1 Phenotype: U
Position: C (α-helix-βD Loo) Ref Type: Full
Comments: (Ramadan KM et al 2006).
c.192_193insG TFTAESPSE
Nucleotide: c.192_193insG Mutation Type: Insertion
Domain: Apple 1 Phenotype: I
Position: - Ref Type: Full
Comments: (Quelin et al 2004)
Patient Info: +
Pro48Leu  (66) TAESPSEDP
Nucleotide: c.197C>T Mutation Type: Polymorphism
Domain: Apple 1 Phenotype: None
Position: T (βD-βE Loop) Ref Type: Full
Comments: (Cargill et al 1999).
Pro52Leu  (70) PSEDPTRWF
Nucleotide: c.209C>T Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: S (βD-βE Loop) Ref Type: None
Comments: Unpublished Data From Coagulation factor XI: a database of mutations and polymorphism associated with factor XI deficiency http://www.wienkav.at/kav/factorxi/Faktor_XI_Suche.asp
Arg54Pro  (72) EDPTRWFTC
Nucleotide: 215G>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: T (βD-βE Loop) Ref Type: Full
Comments: Arg54 is part of an elaborated turning loop connecting the fourth and fifth strands. Electrostatic interactions among Arg54, Glu50 and Asp51 help to maintain the loop architecture. The Arg54Pro mutation elliminates these interactions and results in three close Pro residues, making the loop quite rigid and altering its structure and electrostatic surface (Spena S et al 2009).
Patient Info: +
Arg54Stop  (72) EDPTRWFTC
Nucleotide: c.214C>T Mutation Type: Nonsense
Domain: Apple 1 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Abstract
Comments: Mutation in non-Jewish patient (Castaman G et al 2005)
c.218+2T>A DPTRWFTCV
Nucleotide: c.218+2T>A Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: I
Position: - Ref Type: Full
Comments: In silico analysis predicts the loss of the original donor splice site. Mutation might cause the activation of a putative cryptic splice site. If this holds true, the last 26 amino acids of exon 3 would be deleted, and a stop codon would occur 18 amino acids downstream the splice site mutation in exon 4. (Castaman G 2008).
Patient Info: +
c.218+126A>G DPTRWFTCV
Nucleotide: c.218+126A>G Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Quelin et al 2004).
Thr57Ile   (75) LTRWFTCVLK
Nucleotide: c.224C>T Mutation Type: Deletion
Domain: Apple 1 Phenotype: U
Position: E (βE) Ref Type: Full
Comments: Deletion of nucleotide c.170 results in the replacement of Thr57 for an Ile. This deletion causes a frameshift in exon 4 that predicts termination three codons downstream (Thr57Ile fsX4). Thus, this deletion would induce a premature polypeptide termination, which may result in a truncated protein. The authors hypothesise that for the patient in which this mutation was identified, the mutation causes severe FXI deficiency through truncated protein not secreted or unstable.(Quelin F et al 2009).
Cys58Arg  (76) LRWFTCVLKD
Nucleotide: c.226G>C Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: E (βE) Ref Type: Full
Comments: (Mitchell et al., 2006)
Cys58Phe  (76) LRWFTCVLKD
Nucleotide: c.227G>T Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: E (βE) Ref Type: Full
Comments: (Mitchell et al., 2006)
Patient Info: +
Cys58Tyr  (76) LRWFTCVLKD
Nucleotide: c.227G>A Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: E (βE) Ref Type: Full
Comments: Abrogation of FXI secretion. This mutation disrupts the Cys58-Cys28 bond that is one of the three disulphide bonds responsible for correct folding of the apple 1 domain.Expression studies revealed intact FXI dimerization but no secretion at all from BHK cells (Zucker M et al 2007).
Patient Info: +
Pro69Thr  (87) TETLPRVNR
Nucleotide: c.259C>A Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: C (βE-βF Loop) Ref Type: Full
Comments: (Quelin et al., 2005)
Patient Info: +
Gly79Ala  (97) AAISGYSFK
Nucleotide: c.290G>C Mutation Type: Missense
Domain: Apple 1 Phenotype: I
Position: E (βG) Ref Type: Full
Comments: Gly79Ala occurs in the C terminal portion of Ap1 domain, which contains the binding sites for HK, thrombin and prothrombin. Alanine at position 79 is predicted to introduce two novel hydrogen bonds with the nearby Phe41, probably affecting the local conformation of the protein. Gly79 is strictly conserved in four FXI apple domains of all species and also in kallikrein apple domains (Castaman G 2008).
Patient Info: +
Ser81Tyr  (99) ISGYSFKQC
Nucleotide: c.296C>A Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: C (βG-C4 Loop) Ref Type: Full
Comments: Ser81Tyr is fully buried at the end of β-strand G in the Ap1 domain, thus the replacement with a bulky Tyr residue is expected to disrupt the protein folding (Saunders RE et al 2009).
Patient Info: +
c.301_307dupAAGCAAT GYSFKQCSH
Nucleotide: c.301_307dupAAGCAAT Mutation Type: Insertion
Domain: Apple 1 Phenotype: I
Position: - Ref Type: Full
Comments: (Ventura et al 2000)
Patient Info: +
Lys83Arg  (101) GYSFKQCSH
Nucleotide: c.302A>G Mutation Type: Missense
Domain: Apple 1 Phenotype: U
Position: T (βG-C4 Loop) Ref Type: Full
Comments: Lys83 is a highly conserved residue positioned near Cys85, which is involved in Cys2–Cys85 disulphide linkage. Although this substitution involves amino acids with similar physical and chemical properties, the change may affect local conformation. (Hill et al 2005)
Patient Info: +
Gln88Stop  (106) QCSHQISAC
Nucleotide: c.316C>T Mutation Type: Nonsense
Domain: Linker Region Phenotype: I
Position: C (Linker) Ref Type: Full
Comments: (Quelin et al 2004)
Patient Info: +
c.325+1G>A SHQISACNK
Nucleotide: c.325+1G>A Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: (Mitchell et al., 2006) (Duncan EM et al 2008)
Patient Info: +
c.325G>A HQISACNKD
Nucleotide: c.325G>A Mutation Type: Splice Site
Domain: Apple 2 Phenotype: I
Position: - Ref Type: Full
Comments: Being located at the last position of exon 4, within the physiologic donor splice site, this mutation may also affect the correct splicing of the F11 mRNA. RT-PCR assays performed on total RNA demonstrated that Ala91Thr abolishes the physiologic donor splice site causing the skipping of the affected exon, eventually resulting in a frame shift followed by a premature termination codon. This mutation is predicted to lead to the synthesis of truncated FXI proteins, which might be recognised as abnormal by the quality control system of secretory proteins and therefore intracellularly retained and degraded (Guella I et al 2008).
Patient Info: +
Cys92Gly  (110) QISACNKDI
Nucleotide: c.328T>G Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: C (C1) Ref Type: Full
Comments: The Cys92Gly mutation involves the disappearance of the C92-C175 disulfide bond and probably impairs the structure of the second apple domain. Therefore, this mutation could alter the assembly or the secretion of the protein (Quelin et al., 2005)
Patient Info: +
Met102Thr  (120) VDLDMKGIN
Nucleotide: c.359T>C Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: E (βB) Ref Type: Full
Comments: Met102 is a buried residue and is conserved across six species and prekallikrein. Replacement of the hydrophobic non-polar methionine with a hydrophilic polar threonine is likely to be structurally disruptive. Expression studies indicate it is not expressed and type I. This amino acid substitution does not prevent the formation of dimers, despite the established role of the A2 domain in dimer formation. (Mitchell et al., 2006) (Mitchell MJ et al 2007).
Patient Info: +
Gly104Asp  (122) LDMKGINYN
Nucleotide: c.365G>A Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: C (βB-βC Loop) Ref Type: Full
Comments: (Mitchell et al 2003)
Patient Info: +
Gln116Stop  (134) AKSAQECQE
Nucleotide: c.400C>T Mutation Type: Nonsense
Domain: Apple 2 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: (Dossenbach-Glaninger & Hopmeier 2006) (Castaman G et al 2008)
Patient Info: +
Glu117Stop  (135) KSAQECQER
Nucleotide: c.403G>T Mutation Type: Nonsense
Domain: Apple 2 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: The Type II mutation (Glu117Stop) is the most common mutation in Jewish FXI-deficient patients.
Patient Info: +
Cys118Stop  (136) SAQECQERC
Nucleotide: c.408C>A Mutation Type: Nonsense
Domain: Apple 2 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments:
Patient Info: +
Cys122Tyr  (140) CQERCTDDV
Nucleotide: c.419G>A Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: The Cys122Tyr mutation involves the disappearance of the 122–128 loop in the primary structure of the second apple domain and results in a free cysteine that may affect other disulphide bonds (Quelin et al, 2006). Cys122 is buried in an alpha-helix of Ap2 and is part of the Cys122-Cys128 conserved disulphide bridge that is (along with two other conserved disulphide bridges) responsible for the correct folding of the Ap domains. Therefore, the Cys122Tyr mutation is likely to significantlyimpair the folding of the Ap2 domain. Expression studies reveal a secretion defect (Spena S et al 2009).
Patient Info: +
Thr123Met  (141) QERCTDDVH
Nucleotide: c.422C>T Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments: Thr123Met mutation, near Cys122, causes the introduction of a hydrophobic sulfur atom, with loss of highly hydrophilic hydroxyl group within Threonine (Castaman G et al 2008)
Patient Info: +
Asp125Asp  (143) RCTDDVHCH
Nucleotide: c.429C>T Mutation Type: Polymorphism
Domain: Apple 2 Phenotype: None
Position: S (α-helix-βD Loo) Ref Type: Full
Comments: (Ventura et al 2000).
His127Arg  (145) TDDVHCHFF
Nucleotide: c.434A>G Mutation Type: Missense
Domain: Apple 2 Phenotype: U
Position: S (α-helix-βD Loo) Ref Type: Abstract
Comments: His127Arg is adjacent to Cys122-Cys128 disulphide pairing in apple 2 domain responsible for substrate binding site in FXIa (Castaman G et al 2007 ISTH Poster Abstract)
Cys128Stop  (146) DDVHCHFFT
Nucleotide: c.438C>A Mutation Type: Nonsense
Domain: Apple 2 Phenotype: I
Position: C (α-helix-βD Loo) Ref Type: Full
Comments: Founder mutation found in English patients (Peretz et al 1997).
Patient Info: +
Thr132Met  (150) CHFFTYATR
Nucleotide: c.449C>T Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: E (βD) Ref Type: Full
Comments: (Mitchell et al., 2006) (Saunders RE et al 2009).
Patient Info: +
Tyr133Ser  (151) HFFTYATRQ
Nucleotide: c.452A>C Mutation Type: Missense
Domain: Apple 2 Phenotype: I
Position: E (βD) Ref Type: Full
Comments: Transfection experiments with mutant protein confirmed it is expressed at lower levels comparable to normal FXI (Bolton-Maggs et al 2003 Abstract). Expression studies confirm type I phenotype (CRM negative) (Mitchell et al., 2006)
Patient Info: +
Tyr133Cys  (151) HFFTYATRQ
Nucleotide: c.452C>A Mutation Type: Missense
Domain: Apple 2 Phenotype: U
Position: E (βD) Ref Type: Full
Comments:
Patient Info: +
Ala134Pro  (152) FFTYATRQF
Nucleotide: c.454G>C Mutation Type: Missense
Domain: Apple 2 Phenotype: U
Position: E (βD) Ref Type: Abstract
Comments:
Patient Info: +
Arg144Cys  (162) SLEHRNICL
Nucleotide: c.484C>T Mutation Type: Missense
Domain: Apple 2 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Abstract
Comments: (Dossenbach-Glaninger & Hopmeier 2003)
Patient Info: +
c.485+5G>C SLEHRNICL
Nucleotide: c.485+5G>C Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: (Pugh et al 1995)
c.485+23G>C SLEHRNICL
Nucleotide: c.485+23G>C Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Cargill et al 1999)
c.486-431G>A SLEHRNICL
Nucleotide: c.486-431G>A Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Butler & Parsons 1990). (Peretz et al 1997) (Bolton-Maggs et al 2004).
c.486-361C>T SLEHRNICL
Nucleotide: c.486-361C>T Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Bolton-Maggs et al 2004)
c.486-2A>G SLEHRNICL
Nucleotide: c.486-2A>G Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments:
Patient Info: +
Gly155Glu  (173) HTQTGTPTR
Nucleotide: c.521G>A Mutation Type: Missense
Domain: Apple 2 Phenotype: II
Position: S (βE-βF Loop) Ref Type: Full
Comments: Functional effect; disturbs proposed FXIa binding loop (O'Connell et al 2005). It is of note that there is discrepancy in reported FXI:Ag levels, where a Type I disorder was suggested from concordant low FXI:C/FXI:Ag levels in a patient that was assayed twice (Alhaq et al 2000) (Mitchell et al 2003) ; a Type II disorder was suggested in a second patient which had a higher FXI:Ag (64 IU/dl) than FXI:C (43 IU/ dl) (O'Connell et al 2005). In the consensus Ap structure (Saunders RE et al 2009) , Gly155Glu is aligned with Gly245Glu and Gly336Arg. Gly245Glu and Gly336Arg are both Type I mutations. Since this replacement in both Ap3 and Ap4 causes a Type I phenotype, it is possible that the Gly155 replacement would also result in a Type I phenotype within Ap2. This comparison shows more clearly that further study is needed to confirm the effect of the Gly155Glu mutation in the Ap2 domain (Saunders RE et al 2009).
Patient Info: +
Leu172Pro  (190) SGFSLKSCA
Nucleotide: c.569T>C Mutation Type: Missense
Domain: Apple 2 Phenotype: U
Position: C (βG-C4 Loop) Ref Type: Abstract
Comments: (Wu et al 2004 Abstract)
Patient Info: +
c.595+3A>G ALSNLACIR
Nucleotide: c.595+3A>G Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: Abolishes the physiologic donor splice site causing the skipping of the affected exon, eventually resulting in a frameshift followed by a PTC. Therefore, this mutation is predicted to lead to the synthesis of FXI truncated proteins, which might be recognised as abnormal by the quality control system of secretory proteins and therefore intracellularly retained and degraded (Guella I et al 2008)
Patient Info: +
Ala181Val  (199) LSNLACIRD
Nucleotide: c.596C>T Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: C (Linker) Ref Type: Full
Comments: Ala181 is located next to the conserved cysteine residue 182 that forms a disulphide bridge with Cys265 connecting the two ends of the A3 domain. The Ala181Val substitution possibly interferes with the disulphide bond leading to a misfolded protein (de Raucourt E et al 2008)
Patient Info: +
Cys182Tyr  (200) SNLACIRDI
Nucleotide: c.599G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: C (C1) Ref Type: Abstract
Comments: (Bolton-Maggs et al 2003 Abstract) (Duncan EM et al 2008)
Patient Info: +
Arg184Gly  (202) LACIRDIFP
Nucleotide: c.604A>G Mutation Type: Missense
Domain: Apple 3 Phenotype: II
Position: C (C1-βA Loop) Ref Type: Full
Comments: Transfection experiments of Arg184Gly-FXI, a 70% reduction in FXI activity was observed, suggesting that the Arg184Gly mutation might represent a CRM+ defect (Guella I et al 2008)
Patient Info: +
Pro188Ser  (206) RDIFPNTVF
Nucleotide: c.616T>C Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: E (βA) Ref Type: Full
Comments: (Quelin et al, 2006)
Patient Info: +
c.644-649delTCGACA ADSNIDSVM
Nucleotide: c.644-649delTCGACA Mutation Type: Deletion
Domain: Apple 3 Phenotype: I
Position: - Ref Type: Full
Comments: Expression of recombinant deleted FXI in cos cells indicated impaired secretion as antigen levels were reduced by 83% relative to wild type. Intracellular levels of mutan t protein suggest that the secretion defect does not cause intracellular accumulation of the mutant protein. (Zadra et al, 2004)
Patient Info: +
Asp198Asn  (216) DSNIDSVMA
Nucleotide: c.646G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: E (βC) Ref Type: Abstract
Comments: Hopmeier et al. J Lab Med 2004;28(2):late abstracts
Arg210Stop  (228) FVCGRICTH
Nucleotide: c.682C>T Mutation Type: Nonsense
Domain: Apple 3 Phenotype: I
Position: H (α-helix) Ref Type: Full
Comments:
Patient Info: +
Cys212Ser  (230) CGRICTHHP
Nucleotide: c.688T>A Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: H (α-helix) Ref Type: Full
Comments: Cys212Ser in exon 7 is responsible for suppression of a disulphide bond that maintains the 212-218 loop in the tertiary structure of the third apple domain. It is also possible that free cysteine affects other disulphide bonds such as the 208-237 one. Aberrant or absent disulphide bonds may disrupt the protein structure leading to impaired secretion or function or increased clearance of misfolded proteins. Another mutation involving Cys212 has been described (Cys212Arg). The Cys212 residue is buried. As a consequence, the size or charge of the substituting Arg residue may contribute to protein structure disruption. In Cys212Ser however, neither size nor charge can account for the structure disruption, rather the suppression of disulphide bridges is likely to be the determinant of altered secretion (Quelin F et al 2009)
Patient Info: +
Cys212Arg  (230) CGRICTHHP
Nucleotide: c.688T>C Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: H (α-helix) Ref Type: Abstract
Comments:
Patient Info: +
Phe221Ser  (239) GCLFFTFFS
Nucleotide: c.716T>C Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: E (βD) Ref Type: Full
Comments: Medium of cells transfected with mutant protein contained 5% of the FXI activity secreted by wild type cells. (Morishita et al 2003 Abstract). Transient expression experiment revealed secretion of Phe221Ser FXI was significantly reduced compared with that of wild-type FXI (Okumura K et al 2006)
Patient Info: +
c.717insT CLFFTFFSQ
Nucleotide: c.717insT Mutation Type: Insertion
Domain: Apple 3 Phenotype: U
Position: - Ref Type: Full
Comments: This mutation causes a frameshift at Thr220 and is likely to severely disrupt synthesis of normal protein. (Duncan EM et al 2008).
Patient Info: +
Ser225Phe  (243) FTFFSQEWP
Nucleotide: c.728C>T Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: C (βD-βE Loop) Ref Type: Full
Comments: In single transient transfections, FXI-Phe225 levels in media are low compared with FXI-Wild-Type (WT). This appears to be due to reduced secretion, as FXI-Phe225 levels in lysates are comparable to FXI-WT. Co-transfection of FXI-WT with FXI-Phe225 results in reduced FXI in media compared with FXI-WT control, with little change in intracellular protein. Western blots of intracellular protein shows that FXI-Phe225 forms intracellular dimers similar to FXI-WT, indicating that poor secretion of this mutant is not due to a failure to form dimers (Kravtsov et al 2005).
Patient Info: +
Gln226Stop  (244) TFFSQEWPK
Nucleotide: c.730C>T Mutation Type: Nonsense
Domain: Apple 3 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Full
Comments: (Okumura K et al 2006)
Patient Info: +
Glu226Arg  (244) TFFSQEWPK
Nucleotide: c.731A>G Mutation Type: Polymorphism
Domain: Apple 3 Phenotype: None
Position: T (βD-βE Loop) Ref Type: Full
Comments: Catalytic efficiency of FIX with mutant protein is similar to wild type protein. Mutant protein is associated with reduced hepatic secretion (Sun et al 2001). This mutation is seen in compound heterzygosity but FXI:C is consitant with a partial deficiency and is likely a polymorphism (O'Connell et al 2005).
Patient Info: +
Trp228Stop  (246) FSQEWPKES
Nucleotide: c.738G>A Mutation Type: Nonsense
Domain: Apple 3 Phenotype: U
Position: C (βD-βE Loop) Ref Type: Abstract
Comments:
Patient Info: +
Trp228Cys  (246) FSQEWPKES
Nucleotide: c.738G>C Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: C (βD-βE Loop) Ref Type: Full
Comments: The introduction of a extra cysteine residue within the third apple domain of FXI may result in mis-pairing of disulphide bridges resulting in an altered unstable conformation of the molecule, targeting it for degradation within the cell. Also the missense mutation may be less efficiently secreted from the cell. Either mechanism would explain the CRM-negative phenotype which is usually seen in FXI deficiency (Alhaq et al 1999)
Patient Info: +
Gln233Stop  (251) PKESQRNLC
Nucleotide: c.751C>T Mutation Type: Nonsense
Domain: Apple 3 Phenotype: I
Position: G (βD-βE Loop) Ref Type: Full
Comments: (Mitchell et al., 2006)
Patient Info: +
Arg234Lys  (252) KESQRNLCL
Nucleotide: c.755G Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Full
Comments: Hydrophilic basic arginine is replaced with a hydrophilic basic lysine. The mutation occurs in the last nucleotide of exon 7 and most likely disrupts a normal mRNA splicing (Duncan EM et al 2008).
Patient Info: +
Arg234Ile  (252) KESQRNLCL
Nucleotide: c.755G>T Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Abstract
Comments: (Bolton-Maggs et al 2003 Abstract)
Arg234Ser  (252) KESQRNLCL
Nucleotide: c.756A>T Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: T (βD-βE Loop) Ref Type: Full
Comments:
Patient Info: +
Cys237Tyr  (255) QRNLCLLKT
Nucleotide: c.764G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: E (βE) Ref Type: Full
Comments: Expression studies showed that although mutant protein was synthesised in BHK transfected cells, it was not secreted. The medium of cells transfected with recombinant Cys237Tyr contained 3% of factor XI antigen secreted by normal cells but no demonstrable factor XI activity. The Cys237Tyr mutation disrupts the C208-C237 bond in apple domain 3 (Zivelin et al 2002).
Patient Info: +
c.769delC RNLCLLKTS
Nucleotide: c.769delC Mutation Type: Deletion
Domain: Apple 1 Phenotype: U
Position: - Ref Type: Full
Comments: Leads to a frameshift (Vasileiadis I et al 2009).
Patient Info: +
Glu243Asp  (261) LKTSESGLP
Nucleotide: c.783G>C Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: S (βE-βF Loop) Ref Type: Full
Comments:
Patient Info: +
Gly245Glu  (263) TSESGLPST
Nucleotide: c.788G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: S (βE-βF Loop) Ref Type: Full
Comments: (Hill et al 2005)
Patient Info: +
Ser248Asn  (266) SGLPSTRIK
Nucleotide: c.797G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: II
Position: S (βE-βF Loop) Ref Type: Full
Comments: Mutant protein activates FXI normally in purified protein system and has normal activity, however activation of mutant protein by thrombin in presence of activated platelets is slower than normal. The mutation is associated with reduction in affinity for platelets. (Sun et al 2001).
Patient Info: +
Thr249Thr  (267) GLPSTRIKK
Nucleotide: c.801A>G Mutation Type: Polymorphism
Domain: Apple 3 Phenotype: None
Position: C (βE-βF Loop) Ref Type: Full
Comments: (Ventura et al 2000). Frequency in a random sample of normal volunteers is 19% (Martincic et al 1998).
Arg250Cys  (268) LPSTRIKKS
Nucleotide: c.802C>T Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: C (βE-βF Loop) Ref Type: Abstract
Comments: (Bolton-Maggs et al 2003 Abstract)
Patient Info: +
Arg250His  (268) LPSTRIKKS
Nucleotide: c.803G>A Mutation Type: Missense
Domain: Apple 3 Phenotype: U
Position: C (βE-βF Loop) Ref Type: Full
Comments: Homologue scanning mutagenesis studies of conformationally constrained synthetic peptides identified amino acid residues Arg250 (and Lys255) as being important for binding of FXI to platelets (Ho DH et al 2000). However, the amino acid change at Arg250His is less likely to cause disruption than the FXI Arg250Cys substitution (Duncan EM et al 2008).
Patient Info: +
Lys252Ile  (270) STRIKKSKA
Nucleotide: c.809A>T Mutation Type: Missense
Domain: Apple 3 Phenotype: I
Position: E (βF) Ref Type: Full
Comments: Expression of mutant proteins in stably transfected cells showed a 73% reduction, but expression of the mutant protein in cell lysates was similar to normal - so mut ant protein was synthesised but secretion was reduced. (Dai et al 2004).
Patient Info: +
Gly259Ser  (277) KALSGFSLQ
Nucleotide: c.829G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: E (βG) Ref Type: None
Comments: Unpublished Data
Patient Info: +
Gln263Stop  (281) GFSLQSCRH
Nucleotide: c.841C>T Mutation Type: Nonsense
Domain: Apple 3 Phenotype: I
Position: G (βG-C4 Loop) Ref Type: Full
Comments:
Patient Info: +
Ile269Ile  (287) CRHSIPVFC
Nucleotide: c.861C>T Mutation Type: Polymorphism
Domain: Apple 3 Phenotype: None
Position: S (Linker) Ref Type: Full
Comments: (Cargill et al 1999).
c.865+2delAAACTGAGAGT HSIPVFCHS
Nucleotide: c.865+2delAAACTGAGAGT Mutation Type: Deletion
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Abstract
Comments: 11 base pair deletion in intron 8 (Castaman G et al 2005 ISTH Poster Abstract)
c.865G>T HSIPVFCHS
Nucleotide: c.865G>T Mutation Type: Splice Site
Domain: Linker Region Phenotype: U
Position: - Ref Type: Full
Comments: As Val271 is the last codon of exon 8, located at its 3' splice donor junction, a mutation at this consensus splice sequence (CA G-GTA to CA C-GTA) is predicted to abolish (calculated splice site consensus value 0) the physiological donor splice site (normal splice consensus value 0.91) for exon 8 and probably results in an abnormal FXI transcript. Evaluation of 50 normal chromosomes from the same geographic region did not reveal this sequence change (Jayandharan et al 2005).
Patient Info: +
Phe283Leu  (301) HDTDFLGEE
Nucleotide: c.901T>C Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: E (βB) Ref Type: Full
Comments: Jewish Type III. Mutant protein was secreted at reduced levels (8%) compared to wild type (Meijers et al 1992). Northern blot analysis demonstrated that wild type an d mutant protein generated similar amounts of mRNA. (Kravtsov et al 2004).
Patient Info: +
c.907delG TDFLGEELD
Nucleotide: c.907delG Mutation Type: Deletion
Domain: Apple 4 Phenotype: U
Position: - Ref Type: Full
Comments: Deletion of nucleotide G in codon 285, which causes a frameshift, leading to a stop codon at 5 codons downstream, and predicts a truncated protein (Zivelin et al 2002).
Patient Info: +
c.918delG LGEELDIVA
Nucleotide: c.918delG Mutation Type: Deletion
Domain: Apple 4 Phenotype: U
Position: - Ref Type: Full
Comments: A 1 bp deletion (g) after codon 288 is predicted to cause a frameshift and premature termination of the protein. FXI antigenic data are not available from this family, however, if secreted, this variant would lack an active catalytic domain. Such FXI mutations generally result in a type I disorder through non-secretion or increased mRNA degradation (Hill et al 2005).
Patient Info: +
Ile290Phe  (308) EELDIVAAK
Nucleotide: c.922A>T Mutation Type: Polymorphism
Domain: Apple 4 Phenotype: None
Position: E (βC) Ref Type: Full
Comments: (Cargill et al 1999).
Ile290Thr  (308) EELDIVAAK
Nucleotide: c.924T>C Mutation Type: Polymorphism
Domain: Apple 1 Phenotype: U
Position: E (βC) Ref Type: Full
Comments: (Hill et al 2005).
c.933-951dupAAAAAGTCACGAGGCCTG DIVAAKSHE
Nucleotide: c.933-951dupAAAAAGTCACGAGGCCTG Mutation Type: Insertion
Domain: Apple 4 Phenotype: U
Position: - Ref Type: None
Comments: 19 nucleotide duplication that disrupts the reading frame in the Ap4 domain (Saunders RE et al 2009).
Patient Info: +
Glu297Lys  (315) AKSHEACQK
Nucleotide: c.943G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: T (βC-βD Loop) Ref Type: Full
Comments: Expression of Glu297Lys in BHK cells revealed impaired secretion (4.5% of wild-type FXI) despite the presence of 70% of wild-type FXI antigen in cell lysate, which was shown to be a dimer by western blot analysis (Zucker M et al 2007).
Patient Info: +
Glu297Stop  (315) AKSHEACQK
Nucleotide: c.943G>T Mutation Type: Nonsense
Domain: Apple 4 Phenotype: U
Position: T (βC-βD Loop) Ref Type: Abstract
Comments: Hopmeier et al. J Lab Med 2004;28(2):late abstracts
Patient Info: +
Leu302Pro  (320) ACQKLCTNA
Nucleotide: c.959T>C Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: H (βC-βD Loop) Ref Type: Full
Comments: Amount of mutant protein secreted from cells in vitro is reduced. Leu 302, occurs adjacent to cysteine 303, which forms a disulfide bond with cysteine 309. Structural predictions indicate that the substitution of proline for leucine 302 causes a helical conformation at residues Cys 299, Gln 300, and Lys 301 of the normal protein to be changed to turn and coil conformations and a turn at Ala 306 to be changed to an extended conformation. These changes in the conformation of the protein might prevent the formation of the Cys 303- Cys 309 disulfide bond, altering the structure of the fourth apple domain (Pugh et al 1995).
c.961_962delTG CQKLCTNAV
Nucleotide: c.961_962delTG Mutation Type: Deletion
Domain: Apple 4 Phenotype: U
Position: - Ref Type: Full
Comments: Deletion causes a frameshift in exon 9 that introduces a termination codon in exon 10; thus this deletion would induce the synthesis of a truncated protein. Since no cross-reacting material was found in the plasma, nonsense-mediated decay is likely to take place (Quelin et al, 2006).
Patient Info: +
Thr304Ile  (322) QKLCTNAVR
Nucleotide: c.965C>T Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: H (βC-βD Loop) Ref Type: Full
Comments: Thr304Ile was introduced into factor XI cDNA by site directed mutagenesis and cloned into pEXV-3. Amount of mutant protein secreted from cells in vitro is reduced (Pugh et al 1995).
Patient Info: +
Val307Phe  (325) CTNAVRCQF
Nucleotide: c.973G>T Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: T (βC-βD Loop) Ref Type: Full
Comments: Val307Phe is located buried at the surface of the Ap4 domain, and lies at the interface between the Ap1 and Ap4 domains, thus this mutation may disrupt the packing between the Ap domains (Saunders RE et al 2009).
Patient Info: +
Arg308Cys  (326) TNAVRCQFF
Nucleotide: c.976C>T Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: T (βC-βD Loop) Ref Type: Full
Comments: Introduction of a Cys residue may disrupt disulphide bridge formation. Arg308 lies close to the part of the Ap4 domain responsible for extensive non-covalent interactions between the FXI monomers. (Saunders RE et al 2009).
Patient Info: +
Cys309Stop  (327) NAVRCQFFT
Nucleotide: c.981C>A Mutation Type: Nonsense
Domain: Apple 4 Phenotype: I
Position: C (βC-βD Loop) Ref Type: Full
Comments: Cys309Stop occurs in apple 4 domain, with disruption of Cys309-Cys303 pairing in the inner loop (Castaman G et al 2008)
Patient Info: +
Thr313Ile  (331) CQFFTYTPA
Nucleotide: c.992C>T Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: E (βD) Ref Type: Full
Comments: Interestingly, this mutation is similar to the Thr33Ile conversion but occurs in Ap4. This threonine residue, Thr313, which is laid in the extended strand positioned after alpha-helix, is conserved in positions 43, 132, 222 and 313 of Apple 1, 2, 3 and 4 domains, respectively. The major role of Apple 4 is to mediate dimer formation of two identical polypeptide chains and the Thr313Ile change may distort the conformation of the Apple 4 domain and interfere with its function.(Fard-Esfahani P et al 2008).
Patient Info: +
Cys321Phe  (339) AQASCNEGK
Nucleotide: c.1016G>T Mutation Type: Polymorphism
Domain: Apple 4 Phenotype: None
Position: T (βD-βE Loop) Ref Type: Full
Comments: Cys321 pairs with other Cys321 of Ap4 at dimerisation - however it is not required for dimerisation (Meijers 1992). SDS-PAGE analysis revealed only monomer of FXI present, but mutant protein expressed in BHK cells and normal FXI secretion and activity was present (Zivelin et al 2002).
Glu323Lys  (341) ASCNEGKGK
Nucleotide: c.1021G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: C (βD-βE Loop) Ref Type: Full
Comments: Glu323 lies close to the part of the Ap4 domain responsible for extensive non-covalent interactions between the FXI monomers (Saunders RE et al 2009). Amount of mutant protein secreted from cells in vitro is reduced (Pugh et al 1995).
Patient Info: +
c.1026G>T SCNEGKGKC
Nucleotide: c.1026G>T Mutation Type: Splice Site
Domain: Apple 4 Phenotype: I
Position: - Ref Type: Full
Comments: The alteration (FXI 1026G_T, codon 324) is predicted to affect pre-mRNA splicing and is a synonymous codon change (GGG_GGT) at codon G324 in exon 9. creates a new donor splice site. This frameshift alteration will introduce a premature stop codon at codon 330 (Ventura et al 2000).
Patient Info: +
c.1026dupG SCNEGKGKC
Nucleotide: c.1026dupG Mutation Type: Insertion
Domain: Apple 4 Phenotype: U
Position: - Ref Type: Full
Comments: (Dossenbach-Glaninger et al 2001)
Patient Info: +
c.1028+5G>T CNEGKGKCY
Nucleotide: c.1028+5G>T Mutation Type: Splice Site
Domain: Apple 4 Phenotype: U
Position: - Ref Type: Full
Comments: This FXI mutation abolishes the splice site at the 3' boundary of exon 9 (Saunders RE et al 2009)
Patient Info: +
c.1029-2A>G NEGKGKCYL
Nucleotide: c.1029-2A>G Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: I
Position: - Ref Type: Full
Comments: (Pugh et al 1995)
Gly336Arg  (354) LSSNGSPTK
Nucleotide: c.1060G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: S (βE-βF Loop) Ref Type: Full
Comments:
Patient Info: +
c.1072delA GSPTKILHG
Nucleotide: c.1072delA Mutation Type: Deletion
Domain: Apple 4 Phenotype: I
Position: - Ref Type:
Comments:
Patient Info: +
Ile341Met  (359) SPTKILHGR
Nucleotide: c.1077A>G Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: E (βF) Ref Type: Full
Comments: Ile341 is one of fourteen residues involved in the non-covalent interactions between two Ap4 domains in a FXI dimer. Interestingly, only Ile341Met of these contact residues is reported as a missense mutation, indicating that these contact residues are generally unimportant for FXI deficiency (Saunders RE et al 2009)
Patient Info: +
Leu342Pro  (360) PTKILHGRG
Nucleotide: c.1079T>C Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: C (βF-βG Loop) Ref Type: Full
Comments: This non-conservative change in the surface region of the Apple 4 domain, where active FXII attaches to, converts hydrophobic and moderately sized leucine amino acid to hydrophobic, large proline. Also, amino acids (A317–G350) in this domain contain b strands that interact with FXIIa, the factor which activates FXI [14]. Therefore, substitution of these amino acids may lead to changes in the contact surface conformation and prevents appropriate activation of FXI (Fard-Esfahani P et al 2008).
Patient Info: +
Gly344Arg  (362) KILHGRGGI
Nucleotide: c.1084 Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: S (βF-βG Loop) Ref Type: Full
Comments:
Patient Info: +
Gly350Arg  (368) GGISGYTLR
Nucleotide: c.1102G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: E (βG) Ref Type: Full
Comments: The Gly350Arg mutant is thought not to be secreted as the patient in which the mutation was found shows a parallel defect of both FXI:C and FXI:Ag levels.(Quelin F et al 2009)
Patient Info: +
Gly350Glu  (368) GGISGYTLR
Nucleotide: c.1103G>A Mutation Type: Missense
Domain: Apple 4 Phenotype: I
Position: E (βG) Ref Type: Full
Comments: FXI-Gly350Glu (FXI-Nagoya II), with a more profound defect in dimerisation than FXI-Phe283Leu, would not be expected to influence secretion of wild-type protein appreciably, as was observed in co-transfection experiments. Northern blot analysis demonstrated that wild type and mutant protein generated similar amounts of mRNA. (Kravtsov et al 2004).
Gly350Ala  (368) GGISGYTLR
Nucleotide: c.1103G>C Mutation Type: Missense
Domain: Apple 4 Phenotype: II
Position: E (βG) Ref Type: Full
Comments: Decreases FXI dimerisation (Saunders RE et al 2009)
Patient Info: +
Tyr351Ser  (369) GISGYTLRL
Nucleotide: c.1106A>C Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: E (βG) Ref Type: Full
Comments: Tyr351 is highly conserved in the FXI amino acid sequences or related proteases of different species, indicating the importance of this residue to the structure of apple 4 domain in FXIa. Apple 4 domain is important for the dimerisation of FXIa. A missense substitution at the adjoining residue Gly350Glu (factor XI Nagoya II) has been demonstrated by expression studies (Kravtsov et al 2004) to have a profound effect on FXIa dimerization. It is possible that Tyr351Ser could have a similar effect on FXIa dimerisation(Jayandharan et al 2005).
Patient Info: +
Tyr351Stop  (369) GISGYTLRL
Nucleotide: c.1107C>A Mutation Type: Nonsense
Domain: Apple 4 Phenotype: U
Position: E (βG) Ref Type: Full
Comments:
Patient Info: +
Leu355Ser  (373) YTLRLCKMD
Nucleotide: c.1118T>C Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: T (βG-C4 Loop) Ref Type: Full
Comments: May disrupt a neighbouring disulphide bridge (Saunders RE et al 2009).
Patient Info: +
Cys356Arg  (374) TLRLCKMDN
Nucleotide: c.1120T>C Mutation Type: Missense
Domain: Apple 4 Phenotype: U
Position: G (C4) Ref Type: Full
Comments: Disrupts Cys273-Cys356 disulphide bridge (Saunders RE et al 2009).
Patient Info: +
c.1135+5G>A CKMDNECTT
Nucleotide: c.1135+5G>A Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments:
Patient Info: +
c.1135+1G>A KMDNECTTK
Nucleotide: c.1135+1G>A Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: Mutation changes an invariant nucleotide of the splicing site recognition sequence, and likely results in aberrant splicing of FXI mRNA causing FXI deficiency (Okumura K et al 2006).
Patient Info: +
c.1136-4delGTTG KMDNECTTK
Nucleotide: c.1136-4delGTTG Mutation Type: Deletion
Domain: Introgenic Region Phenotype: I
Position: - Ref Type: Full
Comments: (Xie et al, 2005)
Patient Info: +
Val371Ile  (389) KPRIVGGTA
Nucleotide: c.1165G>A Mutation Type: Missense
Domain: SP Phenotype: II
Position: C (Loop to βB) Ref Type: Full
Comments: Residue Val371 is located one residue following the cleavage site of FXI (P2' position, according to the convention of numbering position around the scissile bond), thus is part of the activation loop. FXI antigen levels, measured in both conditioned media and lysates of cells expressing the mutant protein (in either the heterozygous or homozygous state), were not significantly different from those measured in wild-type samples. FXI specific activity was measured in conditioned media as the ratio between FXI:C and FXI:Ag levels. The specific activity of the FXI–Val371Ile protein was significantly reduced when compared with the wildtype one (30 and 80% for the heterozygous and the homozygous condition, respectively). Given the proximity of Val371 to the FXI activation site, a possible interference on FXI activation was hypothesized and this mutation was found to be associated with a defect both in FXI activation (slower than normal), and in FIX activation (slightly delayed), thus supporting the role of residues neighboring the active site in influencing and stabilizing the enzyme active state.(Bozzao C et al 2007).
Patient Info: +
Gly372Ala  (390) PRIVGGTAS
Nucleotide: c.1169G>C Mutation Type: Missense
Domain: SP Phenotype: U
Position: S (Loop to βB) Ref Type: Full
Comments: (Karimi M et al 2009).
Patient Info: +
Ala375Val  (393) VGGTASVRG
Nucleotide: c.1178C>T Mutation Type: Missense
Domain: SP Phenotype: II
Position: S (Loop to βB) Ref Type: Full
Comments: Ala375Val is exposed in the SP domain on the opposite side of where the His413-Asp462-Ser557 catalytic triad at the active site is located; however, its effect is not clear from the FXI structure (Saunders RE et al 2009).
Patient Info: +
Arg378Cys  (396) TASVRGEWP
Nucleotide: c.1132C>T Mutation Type: Missense
Domain: SP Phenotype: II
Position: T (Loop to βB) Ref Type: Full
Comments: Expression studies indicate that this is a causative mutation (rather than a benign polymorphism (Germanos-Haddad et al 2003)) FXI antigen assays confirm that FXI-Cys378 is secreted. FXI activity assays show FXI-Cys378 to have minimal activity, demonstrating that it is functionally inactive in an APTT-based assay. If, as is suggested in the Germanos-Haddad abstract, Arg378Cys is identified in the 'normal' lebanese population, thus leading to it being misassigned as a polymorphism, then it is possible that it is a common founder mutation. (Mitchell MJ et al 2007).
Patient Info: +
Gly379Gly  (397) ASVRGEWPW
Nucleotide: c.1191T>C Mutation Type: Polymorphism
Domain: SP Phenotype: None
Position: T (Loop to βB) Ref Type: Full
Comments: Frequency in a random sample of normal volunteers is 18% (Martincic et al 1998).
Trp381Leu  (399) VRGEWPWQV
Nucleotide: C.1196G>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: S (Loop to βB) Ref Type: Full
Comments: This mutant is not secreted as in the patient the antigen decrease paralleled the activity decrease (40 and 35 u/dl, respectively). The altered secretion is a more likely mechanism for the defect, because tryptophan substituted for a leucine is not expected to induce major changes in the structure of the catalytic domain, as they are altogether hydrophobic amino acids (Quelin F et al 2009).
Patient Info: +
Trp381Arg  (399) VRGEWPWQV
Nucleotide: c.1195T>C Mutation Type: Polymorphism
Domain: SP Phenotype: None
Position: S (Loop to βB) Ref Type: None
Comments: rs1800439
Pro382Leu  (400) RGEWPWQVT
Nucleotide: c.1199C>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: T (Loop to βB) Ref Type: Full
Comments:
Patient Info: +
Trp383Stop  (401) GEWPWQVTL
Nucleotide: c. 1202G>A Mutation Type: Nonsense
Domain: SP Phenotype: U
Position: T (Loop to βB) Ref Type: Abstract
Comments:
Patient Info: +
Thr386Asn  (404) PWQVTLHTT
Nucleotide: c.1211C>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βB) Ref Type: Full
Comments:
Patient Info: +
His388Pro  (406) QVTLHTTSP
Nucleotide: c.1217A>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βB) Ref Type: Full
Comments: His388 is not charged but is involved in two polar contacts with Arg425 on the opposite beta strand. A turn induced by a proline is likely to disrupt the beta sheet structure (de Raucourt E et al 2008).
Patient Info: +
Thr389Pro  (407) VTLHTTSPT
Nucleotide: c.1219A>C Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βB) Ref Type: Abstract
Comments: (Bolton-Maggs et al 2003 Abstract)
Patient Info: +
Thr390Pro  (408) TLHTTSPTQ
Nucleotide: c.1222A>C Mutation Type: Missense
Domain: SP Phenotype: U
Position: C (βB-βC Loop) Ref Type: None
Comments: Unpublished Data
Patient Info: +
Cys398Tyr  (416) QRHLCGGSI
Nucleotide: c.1247G>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βC) Ref Type: Full
Comments: Mutant protein is not expressed by 293 human kidney fibroblasts (Gailani et al 2001 Abstract). Western blot shows mutant protein forms intracellular dimer. Transfections show reduced secretion of mutant protein. Has a dominant negative effect on wild type secretion. (Kravtsov et al 2005). This mutation breaks the disulphide bridge between Cys398-Cys414 (Saunders RE et al 2009).
Patient Info: +
Gly400Ser  (418) HLCGGSIIG
Nucleotide: c.1252G>A Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βC) Ref Type: Abstract
Comments: Castaman G et al 2007 (ISTH Poster Abstract)
Gly400Val  (418) HLCGGSIIG
Nucleotide: c.1253G>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βC) Ref Type: Full
Comments: Mutant protein is not expressed in 293 kidney fibroblasts (Gailani 2001 et al Abstract B). Northern blot analysis demonstrated that wild type and mutant protein generated similar amounts of mRNA. Co-transfection with wild-type and mutant protein reduces wild-type secretion about 50% - non-secretable mutant protein monomers trap wild-type polypeptides within cells through homodimer formation, resulting in lower FXI levels in plasma. Gly400Val exerts a dominant negative effect which stems froman impaired secretion of heterodimers consisting of a normal and a mutant monomer (Kravtsov et al 2004).
Patient Info: +
Ser401Ala  (419) LCGGSIIGN
Nucleotide: c.1255T>G Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βC) Ref Type: Abstract
Comments: Hopmeier et al. J Lab Med 2004;28(2):late abstracts
Patient Info: +
Gln406Stop  (424) IIGNQWILT
Nucleotide: c.1270C>T Mutation Type: Nonsense
Domain: SP Phenotype: U
Position: S (βC-βD Loop) Ref Type: Full
Comments:
Patient Info: +
Trp407Cys  (425) IGNQWILTA
Nucleotide: c.1275G>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βD) Ref Type: Full
Comments: The low FXI level (22%) observed suggests a domainant negative mutation (de Raucourt E et al 2008). Interestingly, the residues Gly400 (also reported to exert a negative dominant effect (Kravtsov et al 2004)) and Trp407 are located on opposite strands of a beta sheet, and the Trp407 residue establishes polar contacts with Ile403 and Gly404, suggesting that misfolding of this beta sheet could be critical for this dominant negative effect (de Raucourt E et al 2008).
Patient Info: +
Thr410Ile  (428) QWILTAAHC
Nucleotide: c.1283C>T Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βD) Ref Type: Full
Comments: Thr410 occupies a buried position within the FXI SP domain adjacent to His413 of the active site and may perturb either the folding or the function of the SP domain (Saunders RE et al 2009).
Patient Info: +
Ala412Ser  (430) ILTAAHCFY
Nucleotide: c.1288G>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: G (βD-βF Loop) Ref Type: Full
Comments: Ala412Ser occupies a buried position within the SP domain adjacent to His413 of the active site, and may perturb either the folding or function of the SP domain (Saunders RE et al 2009).
Patient Info: +
Ala412Thr  (430) ILTAAHCFY
Nucleotide: c.1288G>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: G (βD-βF Loop) Ref Type: Full
Comments: Ala412 is located in an alpha helix portion, and a threonine at this position is expected to disrupt the helix structure because of the steric constraints caused due to the size of the residues Phe415 and Tyr416 (de Raucourt E et al 2008). The introduction of a polar residue in place of the simple aliphatic side chain of alanine is likely to perturb the local folding of the protein. Homology modelling suggests that this substitution might impair FXI secretion by reducing the stability of the serine protease fold (Castaman G 2008).
Patient Info: +
Ala412Val  (430) ILTAAHCFY
Nucleotide: c.1289C>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: G (βD-βF Loop) Ref Type: Full
Comments: Homology modelling suggests that this substitution may reduce the stability of the serine protease fold, resulting in non-secretion (O'Connell et al 2005)
Patient Info: +
c.1304+12G>A HCFYGVESP
Nucleotide: c.1304+12G>A Mutation Type: Missense
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: Intron 11. (Saunders RE et al 2009)
Patient Info: +
c.1305-10T>A CFYGVESPK
Nucleotide: c.1305-10T>A Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: This mutation, in the polypyrimidine track of the intron K acceptor splice site effects FXI pre-mRNA splicing. It abolishes an AluI restriction site. This creates an alternative splice sites that results in the inclusion of intronic, or deletion of exonic nucleotides leading to frameshift (Ventura et al 2000)
Patient Info: +
Arg425Cys  (443) PKILRVYSG
Nucleotide: c.1327C>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βF) Ref Type: Full
Comments:
Patient Info: +
Cys427Tyr  (445) ILRVYSGIL
Nucleotide: c.1334A>G Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βF) Ref Type: Full
Comments: Expressing Tyr427Cys in BHK cells resulted in abrogation of FXI secretion despite intact dimerisation, and was associated with a reduced amount of FXI in lysed cells (Zucker M et al 2007).
Patient Info: +
Ser428Gly  (446) LRVYSGILN
Nucleotide: c.1336A>G Mutation Type: Polymorphism
Domain: SP Phenotype: U
Position: E (βF) Ref Type: Full
Comments: One small hydrophilic amino acid (Ser) is replaced by another small, hydrophilic amino acid (Gly). Ser428 is conserved in bovine FXI and human prekallikrein, but it is not conserved in rabbit or murine FXI. Family study of four siblings of index patient (FXI:C 47 U/dL)showed presence of mutation is not associated with reduced FXI levels. Furthermore index patient has another possible explanation for reduced FXI level: liver dysfunction. Likely to be a non-causative polymorphism (Duncan EM et al 2008).
Gln433Glu  (451) GILNQSEIK
Nucleotide: c.1394C>G Mutation Type: Missense
Domain: SP Phenotype: U
Position: G (βF-βG Loop) Ref Type: Full
Comments: Expected to lead to disruption of the catalytic domain structure of FXI molecule. Gln433 is highly conserved among humans, cattle, mice and dogs, as well as red jungle fowl, which suggests that Gln433 may be crucial for FXI activity. Gln has no charge, while Glu has a net negative charge at physiological pH. The charge change during Gln to Glu substitution may disturb the electrostatic properties of FXI, leading to abnormal activity (Ishikawa N et al 2007).
Patient Info: +
Phe442Val  (460) EDTSFFGVQ
Nucleotide: c.1378T>G Mutation Type: Missense
Domain: SP Phenotype: I
Position: C (βF-βG Loop) Ref Type: Full
Comments: Oligonucleotide probes of WT and mutant were hybridized to 50 normal individuals. Only WT hydrized - so not a polymorphism. (Imanaka et al 1995).
Patient Info: +
Glu447Stop  (465) FGVQEIIIH
Nucleotide: c.1393G>T Mutation Type: Nonsense
Domain: SP Phenotype: I
Position: E (βG) Ref Type: Full
Comments: The G to A transversion in exon 12 results in a nonsense mutation Glu447Stop which leads to the disruption of the catalytic domain structure of the FXI molecule (Tsukahara et al 2003).
Patient Info: +
Gly460Arg  (478) MAESGYDIA
Nucleotide: c.1432G>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: B (βG-βH Loop) Ref Type: Full
Comments: Mutant protein is expressed at levels comparable to normal FXI, and mutant protein was not secreted (Bolton-Maggs et al 2003 Abstract).
Patient Info: +
Thr475Ile  (493) TVNYTDSQR
Nucleotide: c.1478C>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: B (βH-βj Loop) Ref Type: Full
Comments: Expression of mutation protein shows mutant is secreted poorly compared to wild type. This mutation destroys N-linked glycosylation site. Substitution of Thr475 with Ala, Pro, Lys or Arg all abolish the site and also severely reduce level of secreted FXI:Ag. Substitution with Ser which does not abolish the site had no affect on secretion. However substitution of Asn473 with Ala which abolishes the glycosylation site also had no affect on secretion. This indicates the cause of failure to secrete FXI is not the loss of glycolsylation site. (McVey et al, 2005).
Patient Info: +
c.1480+2T>G VNYTDSQRP
Nucleotide: c.1480+2T>G Mutation Type: Splice Site
Domain: SP Phenotype: U
Position: - Ref Type: Full
Comments: (Zucker M et al 2007)
Patient Info: +
Asp476Stop  (494) VNYTDSQRP
Nucleotide: c.1482T>A/G Mutation Type: Nonsense
Domain: SP Phenotype: U
Position: T (βH-βj Loop) Ref Type: Abstract
Comments: (Bolton-Maggs et al 1999 Abstract)
Arg479Stop  (497) TDSQRPICL
Nucleotide: c.1489C>T Mutation Type: Nonsense
Domain: SP Phenotype: I
Position: C (βH-βj Loop) Ref Type: Full
Comments:
Patient Info: +
Cys482Arg  (500) QRPICLPSK
Nucleotide: c.1498T>C Mutation Type: Missense
Domain: SP Phenotype: U
Position: B (βH-βj Loop) Ref Type: Full
Comments: Cys482Arg breaks the disulphide bridge between Cys482-Cys362 (Saunders RE et al 2009).
Patient Info: +
Cys482Trp  (500) QRPICLPSK
Nucleotide: c.1500C>G Mutation Type: Missense
Domain: SP Phenotype: U
Position: B (βH-βj Loop) Ref Type: Full
Comments: Cys482Trp breaks the disulphide bridge between Cys482-Cys362 (Saunders RE et al 2009).
Patient Info: +
Ser485Pro  (503) ICLPSKGDR
Nucleotide: c.1507T>C Mutation Type: Missense
Domain: SP Phenotype: U
Position: C (βH-βj Loop) Ref Type: Full
Comments: Ser485Pro converts hydrophilic small sized serine to hydrophobic, large proline in the buried region of the serine protease domain. Ser485 is in the random coil area of the structure, and may cause damaging structural effect (Fard-Esfahani P et al 2008).
Patient Info: +
Tyr493His  (511) RNVIYTDCW
Nucleotide: c.1531T>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: C (βH-βj Loop) Ref Type: Full
Comments: Cells transfected with mutant protein contained reduced amounts of FXI and displayed decreased secretion (Zivelin et al 2002).
Patient Info: +
Trp497Cys  (515) YTDCWVTGW
Nucleotide: c.1545G>T Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βJ) Ref Type: Full
Comments:
Patient Info: +
Val498Met  (516) TDCWVTGWG
Nucleotide: c.1546G>A Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βJ) Ref Type: Full
Comments: Val498 residue is highly conserved across different species. The Val498Met mutation generates an ectopic methionine residue close to the disulphide bond between C496 and C563. Bioinformatics study using surface mapping of the evolutionary conservation level revealed that Val498 is a functionally important residue (Kwon MJ et al 2008).
Patient Info: +
c.1556insG WVTGWGYRK
Nucleotide: c.1556insG Mutation Type: Insertion
Domain: SP Phenotype: I
Position: - Ref Type: Full
Comments: 501/502insG
Patient Info: +
Trp501Stop  (519) WVTGWGYRK
Nucleotide: c.1556G>A Mutation Type: Nonsense
Domain: SP Phenotype: I
Position: C (βJ-βK Loop) Ref Type: Full
Comments:
Patient Info: +
Trp501Cys  (519) WVTGWGYRK
Nucleotide: c.1557G>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: C (βJ-βK Loop) Ref Type: Full
Comments:
Patient Info: +
c.1560dupG TGWGYRKLR
Nucleotide: c.1560dupG Mutation Type: Insertion
Domain: SP Phenotype: U
Position: - Ref Type: Full
Comments: Mutations inserts an additional G in a stretch of five guanine nucleotides at nucleotide position 1560. This leads to a frameshift, generating a premature truncation codon at position 535 [Tyr503ValfsX32] (Kwon MJ et al 2008).
Patient Info: +
c.1574-93dupAT YRKLRDKIQ
Nucleotide: c.1574-93dupAT Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Peretz et al 1997).
Lys518Asn  (536) LQKAKIPLV
Nucleotide: c.1608G>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βK) Ref Type: Full
Comments: The novel missense mutation FXI Lys518Asn leads to the replacement of the Lys518 which is part of a LxxxxxPxxxxxxC motif (x-variable amino acid) that occurs in several subfamilies of serine proteases. Although this motif is highly conserved between FXI and pre-kallikrein (86% sequence identity), the Lys518 is not conserved. On the other hand, this residue is conserved in human, murine and bovine FXI indicating that this is a FXI-specific amino acid. A molecular model of FXI predicts that the side-chain of this residue is on the surface of the molecule, possibly H-bonded to W497. Replacement of the positively charged lysine side chain by the smaller, neutral side chain of asparagine may interfere with the folding of the FXI molecule and/or secretion, leading to low antigen level. Alternatively, the secreted FXI variant may have a shortened plasma half-life (Ventura et al 2000).
Patient Info: +
Pro520Leu  (538) KAKIPLVTN
Nucleotide: c.1613C>T Mutation Type: Missense
Domain: SP Phenotype: II
Position: C (βK-α-helix 2 L) Ref Type: Full
Comments: Mutant protein is expressed in 293 human kidney fibroblasts. Activated mutant has a modest catalytic defect in functional assays (Gailani et al 2001 Abstract). The basis of catalytic defect that results from Pro520Leu alteration is due to subtle alterations in the oxyanion hole, which develops during conversion of zymogen to active enzyme, and results in a ~3.5-fold decrease in catalytic efficiency, consistent with the 70-80% loss of activity noted in conventional coagulation assays. Thus, Pro520 is important in maintaining the normal conformation of the FXI active site (Gailani D et al 2007). Pro520 is conserved in FX and FVII, and its mutation in both these other proteins also causes Type II phenotypes (Saunders RE et al 2009).
Patient Info: +
Cys527Tyr  (545) TNEECQKRY
Nucleotide: c.1634G>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: H (α-helix 2) Ref Type: Full
Comments: Expression of Cys527Tyr in BHK cells revealed intact dimerisation, a reduced amount of FXI in lysed cells and total lack of secretion from the cells (Zucker M et al 2007).
Patient Info: +
Gly544Ser  (562) MICAGYREG
Nucleotide: c.1684G>A Mutation Type: Missense
Domain: SP Phenotype: U
Position: C (α-helix 2 - βM) Ref Type: Full
Comments: Gly544Ser resides on a surface exposed loop within the SP domain and it is not clear whether this is the causative mutation because the patient’s mother has the mutation but has normal FXI:C levels (Saunders RE et al 2009).
Patient Info: +
Glu547Lys  (565) AGYREGGKD
Nucleotide: c.1693G>A Mutation Type: Missense
Domain: SP Phenotype: I
Position: C (α-helix 2 - βM) Ref Type: Full
Comments:
Patient Info: +
Asp551Asp  (569) EGGKDACKG
Nucleotide: c.1704C>T Mutation Type: Polymorphism
Domain: SP Phenotype: None
Position: C (α-helix 2 - βM) Ref Type: Full
Comments: (Cargill et al 1999).
c.1714_1716+11del KDACKGDSG
Nucleotide: c.1714_1716+11del Mutation Type: Splice Site
Domain: SP Phenotype: I
Position: - Ref Type: Full
Comments: Jewish Type IV (Peretz H et al 1996).
Patient Info: +
c.1716+1G>A KDACKGDSG
Nucleotide: c.1716+1G>A Mutation Type: Splice Site
Domain: SP Phenotype: I
Position: - Ref Type: Full
Comments: Jewish Type I mutation
Patient Info: +
c.1717-48A>G KDACKGDSG
Nucleotide: c.1717-48A>G Mutation Type: Polymorphism
Domain: Introgenic Region Phenotype: None
Position: - Ref Type: Full
Comments: (Cargill et al 1999).
c.1717-2A>G DACKGDSGG
Nucleotide: c.1717-2A>G Mutation Type: Splice Site
Domain: Introgenic Region Phenotype: U
Position: - Ref Type: Full
Comments: This point mutation interferes with normal splicing and results in a truncated protein (Fard-Esfahani P et al 2008).
Gly555Glu  (573) DACKGDSGG
Nucleotide: c.1718G>A Mutation Type: Missense
Domain: SP Phenotype: II
Position: C (α-helix 2 - βM) Ref Type: Full
Comments: Normal amount of mutant protein secreted from BHK cells (Zivelin et al 2001 Abstract). Experimental data indicates the mutation changes the conformation of the unoccupied active site of FXIa (Schmidt et al 2004). When compared with wild type FXI-Glu555 activates FIX at a greatly reduced rate. Modelling indicates side chain of Glu555 alters electrostatic charge around active site and interferes with the interaction between FXI and FIX and antithrombin. (Zivelin et al 2004).
Patient Info: +
Asp556Gly  (574) ACKGDSGGP
Nucleotide: c.1721A>G Mutation Type: Missense
Domain: SP Phenotype: U
Position: C (α-helix 2 - βM) Ref Type: Abstract
Comments: Castaman G et al 2007 (ISTH Poster Abstract)
Cys563Phe  (581) GPLSCKHNE
Nucleotide: c.1742G>T Mutation Type: Missense
Domain: SP Phenotype: U
Position: E (βM) Ref Type: Full
Comments:
Patient Info: +
Trp569Ser  (587) HNEVWHLVG
Nucleotide: c.1760G>C Mutation Type: Missense
Domain: SP Phenotype: I
Position: E (βN) Ref Type: Full
Comments: Co-transfection with wild-type and mutant protein reduces wild-type secretion about 50% - non-secretable mutant protein monomers trap wild-type polypeptides within cells through homodimer formation, resulting in lower FXI levels in plasma. (Kravtso v et al 2004). Mutant protein is not expressed in 293 kidney fibroblasts (Gailani et al 2001 Abstract B).
Patient Info: +