Missense mutations of coagulation factor XII in hereditary angioedema with normal complement C1 inhibitor

2007 ◽  
Vol 44 (1-3) ◽  
pp. 163
Author(s):  
Georg Dewald ◽  
Konrad Bork
Keyword(s):  
Hereditary Angioedema ◽  
Coagulation Factor ◽  
Factor Xii ◽  
Missense Mutations ◽  
C1 Inhibitor ◽  
Normal Complement

Missense Mutations in the Proline-Rich Region of Coagulation Factor XII in Hereditary and Idiopathic Angioedema.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1619-1619
Author(s):  
Georg Dewald ◽  
Konrad Bork
Keyword(s):  
Hereditary Angioedema ◽  
Coagulation Factor ◽  
Factor Xii ◽  
Missense Mutations ◽  
C1 Inhibitor ◽  
Rich Region ◽  
Female Patients ◽  
Exon 9 ◽  
Idiopathic Angioedema ◽  
Proline Rich Region

Abstract Hereditary angioedema (HAE) is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The two classic HAE types (I and II) are caused by mutations in the complement C1 inhibitor gene, resulting in a functional deficiency of C1 inhibitor. Recently, a novel type of hereditary angioedema has been described, these patients showing normal C1 inhibitor concentration and activity in plasma (HAE with normal C1 inhibitor, HAE type III). With few exceptions, all reported patients have been women, and exposition to estrogens appears to be an important precipitating factor. Screening of twenty unrelated female patients with this new type of HAE for mutations in the coagulation factor XII gene revealed two different missense mutations, both located in exactly the same position within exon 9, namely in the second position of the codon (ACG) encoding Thr309 of the mature protein. Five patients showed a C→A transversion (1032C→A), predicting a threonine-to-lysine substitution (Thr309Lys); one additional patient showed a C→G transversion (1032C→G), resulting in a threonine-to-arginine substitution (Thr309Arg). Thus, in 6 of 20 unrelated patients the wild-type threonine residue is substituted by a basic amino acid residue. The mutations are located in the proline-rich region of factor XII which may play some role in the binding of factor XII to negatively charged surfaces, and, thus, may eventually influence mechanisms of contact activation. The predicted structural and functional impact of the mutations, their absence in healthy control individuals (n=145), and their co-segregation with the phenotype in five families with altogether 20 affected women provide strong support that they cause disease (Biochem. Biophys. Res. Commun.343: 1286–1289, 2006). We speculated if these mutations may also be present in singular angioedema cases, i.e., patients with no affected family members. We therefore studied 58 such patients with idiopathic recurrent angioedema (23 men, 35 women) by sequencing of exon 9 of the F12 gene. In two patients, both female, the 1032C→A (Thr309Lys) mutation was observed. Thus, this mutation may also play a role in a subgroup of patients with idiopathic angioedema, in particular in female patients. The known estrogen-dependent regulation of factor XII expression may well be seen in association with the disease manifestation mainly in women.

scholarly journals Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor

2015 ◽  
Vol 166 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Adriana S. Moreno ◽  
Solange O.R. Valle ◽  
Soloni Levy ◽  
Alfeu T. França ◽  
Faradiba S. Serpa ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Hereditary Angioedema ◽  
Coagulation Factor ◽  
Factor Xii ◽  
C1 Inhibitor

scholarly journals Diagnosis of hereditary Angioedema by genetic mutation of coagulation factor XII

2021 ◽  
Vol 147 (2) ◽  
pp. AB23
Author(s):  
Natasha Ferraroni ◽  
Gabriela Yoshimoto ◽  
Camila Veronez ◽  
Luiza Silva ◽  
Marina Batista ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Coagulation Factor ◽  
Genetic Mutation ◽  
Factor Xii

scholarly journals Review of the Manitoba cohort of patients with hereditary angioedema with normal C1 inhibitor

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Lundy McKibbin ◽  
Colin Barber ◽  
Chrystyna Kalicinsky ◽  
Richard Warrington
Keyword(s):  
Family History ◽  
Tranexamic Acid ◽  
Hereditary Angioedema ◽  
Acute Treatment ◽  
Chart Review ◽  
Positive Family History ◽  
Retrospective Chart Review ◽  
Factor Xii ◽  
C1 Inhibitor ◽  
And Function

Abstract Background Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response. Methods A retrospective chart review of 418 patients diagnosed with angioedema was conducted. The following inclusion criteria was used: lack of response to antihistamines, steroids, and epinephrine; normal C4, C1 inhibitor (C1 INH) level and function; lack of urticaria or pruritus; occurrence without offending drugs; and positive family history. Enzyme immunoassays for C1 INH function were performed at the Mayo Clinic. Charts meeting these criteria were reviewed for frequency and type of episodes as well as use and response to therapies. Results 6 patients met the above criteria. 3 of these completed genetic testing, none were found to have factor XII abnormalities. None had angiopoietin 1 or plasminogen gene sequencing. 5 of 6 patients were successfully treated with C1 INH or tranexamic acid for acute treatment of attacks (4 with C1 INH and 1 with tranexamic acid). 4 patients have used Icatibant with good response (typically under 40 min for near full recovery); of these, 3 required Icatibant as acute treatment after other therapies (C1 inhibitor and tranexamic acid) were ineffective. There were 9 patients who otherwise met criteria, but due to a lack of family history were classified as having idiopathic non-histaminergic angioedema. Conclusions This retrospective chart review found 6 HAE-nC1 INH patients in Manitoba. 1 responded to tranexamic acid and not C1 INH, 4 typically responded to C1 INH, and 1 responded exclusively to Icatibant. All patients—4 total—who used Icatibant responded; of these 4 patients, 3 required Icatibant after other therapies had failed.

scholarly journals A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1152-1163 ◽  
Author(s):  
Ivan Ivanov ◽  
Anton Matafonov ◽  
Mao-fu Sun ◽  
Bassem M. Mohammed ◽  
Qiufang Cheng ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Hereditary Angioedema ◽  
Catalytic Efficiency ◽  
Regulatory Function ◽  
Factor Xii ◽  
C1 Inhibitor ◽  
Contact Activation ◽  
Inhibitory Function

Abstract The plasma proteins factor XII (FXII) and prekallikrein (PK) undergo reciprocal activation to the proteases FXIIa and kallikrein by a process that is enhanced by surfaces (contact activation) and regulated by the serpin C1 inhibitor. Kallikrein cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin. Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Although most HAE cases are caused by reduced plasma C1-inhibitor activity, HAE has been linked to lysine/arginine substitutions for Thr309 in FXII (FXII-Lys/Arg309). Here, we show that FXII-Lys/Arg309 is susceptible to cleavage after residue 309 by coagulation proteases (thrombin and FXIa), resulting in generation of a truncated form of FXII (δFXII). The catalytic efficiency of δFXII activation by kallikrein is 15-fold greater than for full-length FXII. The enhanced rate of reciprocal activation of PK and δFXII in human plasma and in mice appears to overwhelm the normal inhibitory function of C1 inhibitor, leading to increased HK cleavage. In mice given human FXII-Lys/Arg309, induction of thrombin generation by infusion of tissue factor results in enhanced HK cleavage as a consequence of δFXII formation. The effects of δFXII in vitro and in vivo are reproduced when wild-type FXII is bound by an antibody to the FXII heavy chain (HC; 15H8). The results contribute to our understanding of the predisposition of patients carrying FXII-Lys/Arg309 to angioedema after trauma, and reveal a regulatory function for the FXII HC that normally limits PK activation in plasma.

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