In silicoanalyses of missense mutations in coagulation factor VIII: identification of severity determinants of haemophilia A

Haemophilia ◽  
2015 ◽  
Vol 21 (5) ◽  
pp. 662-669 ◽  
Author(s):  
M. Sengupta ◽  
D. Sarkar ◽  
K. Ganguly ◽  
D. Sengupta ◽  
S. Bhaskar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Haemophilia A ◽  
Missense Mutations

Molecular simulation studies of human coagulation factor VIII C domain-mediated membrane binding

2015 ◽  
Vol 113 (02) ◽  
pp. 373-384 ◽  
Author(s):  
Jiangfeng Du ◽  
Kanin Wichapong ◽  
Tilman M. Hackeng ◽  
Gerry A. F Nicolaes
Keyword(s):  
Factor Viii ◽  
Membrane Binding ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Haemophilia A ◽  
C2 Domain ◽  
Missense Mutations ◽  
C2 Domains ◽  
C1 Domain ◽  
Dynamics Simulations

SummaryThe C-terminal C domains of activated coagulation factor VIII (FVIIIa) are essential to membrane binding of this crucial coagulation cofactor protein. To provide an overall membrane binding mechanism for FVIII, we performed simulations of membrane binding through coarsegrained molecular dynamics simulations of the C1 and C2 domain, and the combined C-domains (C1+C2). We found that the C1 and C2 domain have different membrane binding properties. The C1 domain uses hydrophobic spikes 3 and 4, of its total of four spikes, as major loops to bind the membrane, whereas all four of its hydrophobic loops of the C2 domain appear essential for membrane binding. Interestingly, in the C1+C2 system, we observed cooperative binding of the C1 and C2 domains such that all four C2 domain spikes bound first, after which all four loops of the C1 domain inserted into the membrane, while the net binding energy was higher than that of the sum of the isolated C domains. Several residues, mutations of which are known to cause haemophilia A, were identified as key residues for membrane binding. In addition to these known residues, we identified residues from the C1 and C2 domains, which are involved in the membrane binding process, that have not been reported before as a cause for haemophilia A, but which contribute to overall membrane binding and which are likely candidates for novel causative missense mutations in haemophilia A.

F VIII Inhibitors in Haemophilia A Patients after Continuous Infusion of Factor VIII Concentrates.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3100-3100
Author(s):  
Ch. von Auer ◽  
J. Oldenburg ◽  
M. von Depka ◽  
C. Escuriola-Ettinghausen ◽  
W. Kreuz ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Orthopaedic Surgery ◽  
Coagulation Factor ◽  
Haemophilia A ◽  
Missense Mutations ◽  
Factor Viii Concentrates ◽  
Coagulation Factor Concentrates ◽  
Major Orthopaedic Surgery ◽  
Mild Haemophilia

Abstract Continuous infusion (CI) of coagulation factor concentrates has been used since the early 1990s. Recent reports of the occurrence of an inhibitor (inh) after CI have raised concerns about this method of treatment. We conduct a retrospective study to investigate the development of inh after CI of FVIII concentrates in Germany. 99 haemophilia treating physicians in Germany were contacted and asked to answer a questionnaire. So far data of 13 departments have been reported and analyzed. Three of these 13 centers never conducted a CI, in 5 no inh were detected and in 5 haemophilia centers 10 patients with inh development after CI were registered. 5 of these patients were suffering from severe, 1 from moderate and 4 from mild haemophilia (age between 7 months and 57 years). Indications for treatment were major bleeds and surgical procedures. Plasma derived (6) and recombinant (4) factor concentrates were given in various infusion sets. Data concerning infused amount (4300 to >100000 IE), exposure days (1 to >100) and inh characteristic (alloantibodies, 3 LR, 7 HR) were collected. Regarding the genotype, we found 4 missense-mutations, 2 intron-22-inversions, 1 small deletion, 3 were unknown. In our own center we found no inh in 81 patients with major orthopaedic surgery and bolus infusion of factor VIII concentrate compared to 2 inh in 8 patients with major orthopaedic surgery and CI of FVIII. In conclusion we found only in 2 patients the typical gene mutation for inh development. Strikingly the inh developed very often in patients with mild haemophilia. These findings agree with published results. There might be an uncommon inh-pathomechanism due to CI or patients with mild haemophilia might exhibit a much higher prevalence of inhibitor development when treated with an “intensive FVIII-treatment” such as CI.

Promising coagulation factor VIII bypassing strategies for patients with haemophilia A

2014 ◽  
Vol 25 (6) ◽  
pp. 539-552 ◽  
Author(s):  
Xunwei Duan ◽  
Mingqing Tang ◽  
Junping Zhang ◽  
Hao Yu ◽  
Ruian Xu
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Haemophilia A

scholarly journals Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII

2018 ◽  
Vol 475 (5) ◽  
pp. 873-886 ◽  
Author(s):  
Wei Wei ◽  
Saurav Misra ◽  
Matthew V. Cannon ◽  
Renchi Yang ◽  
Xiaofan Zhu ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Factor Viii ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Severe Disease ◽  
Coagulation Factor ◽  
Relative Activity ◽  
Coagulation Factor Viii ◽  
Missense Mutations ◽  
Glycosylation Sites

N-glycosylation is a common posttranslational modification of secreted and membrane proteins, catalyzed by the two enzymatic isoforms of the oligosaccharyltransferase, STT3A and STT3B. Missense mutations are the most common mutations in inherited diseases; however, missense mutations that generate extra, non-native N-glycosylation sites have not been well characterized. Coagulation factor VIII (FVIII) contains five consensus N-glycosylation sites outside its functionally dispensable B domain. We developed a computer program that identified hemophilia A mutations in FVIII that can potentially create ectopic glycosylation sites. We determined that 18 of these ectopic sites indeed become N-glycosylated. These sites span the domains of FVIII and are primarily associated with a severe disease phenotype. Using STT3A and STT3B knockout cells, we determined that ectopic glycosylation exhibited different degrees of dependence on STT3A and STT3B. By separating the effects of ectopic N-glycosylation from those due to underlying amino acid changes, we showed that ectopic glycans promote the secretion of some mutants, but impair the secretion of others. However, ectopic glycans that enhanced secretion could not functionally replace a native N-glycan in the same domain. Secretion-deficient mutants, but not mutants with elevated secretion levels, show increased association with the endoplasmic reticulum chaperones BiP (immunoglobulin heavy chain-binding protein) and calreticulin. Though secreted to different extents, all studied mutants exhibited lower relative activity than wild-type FVIII. Our results reveal differential impacts of ectopic N-glycosylation on FVIII folding, trafficking and activity, which highlight complex disease-causing mechanisms of FVIII missense mutations. Our findings are relevant to other secreted and membrane proteins with mutations that generate ectopic N-glycans.

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