In Silica Study of Correlation between Missense Variations of F8 Gene and Inhibitor Formation in Severe Hemophilia A

被引:2
作者
Fodil, Mostefa [1 ]
Zemani, Faouzia [2 ]
机构
[1] Higher Sch Biol Sci Oran ESSBO, Oran, Algeria
[2] Oran Univ Sci & Technol Mohamed Boudiaf USTOMB, Mol & Cellular Genet Lab, Oran, Algeria
关键词
Hemophilia A; Missense variation; In silico analysis; Inhibitor formation; FVIII; Coagulation; COAGULATION-FACTOR VIII; RISK-FACTORS; MUTATIONS; IDENTIFICATION;
D O I
10.4274/tjh.galenos.2019.2019.0094
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Deleterious substitutions of the F8 gene are responsible for causing hemophilia A, which is an inherited bleeding disorder resulting from reduced or absent activity of the coagulant protein factor VIII (FVIII). The most important complication in treatment is inhibitor development toward therapeutic factor VIII. In this study, we aimed to analyze the effects of deleterious substitutions in the F8 gene upon protein structure and function. Materials and Methods: All tests were conducted by computational methods from the CHAMP (CDC Hemophilia A Mutation Project) database. We performed an in silico analysis of deleterious variations using five software programs, Sift, PolyPhen-2, Align-GVGD, KD4v, and MutationTaster, in order to analyze the correlation between variation and the disease. We also studied the correlation between these variations and inhibitor formation. Results: Our analysis showed that these in silico tools are coherent and that there are more variations in the A than the C domains. Moreover, we noticed that there are more deleterious variations than neutral variations in each of the A and C domains. We also found that 13.51% of the patients suffered from a severe form of hemophilia A and that carriers of missense variations developed inhibitors. Also, for the first time, we determined that variation nature is not associated with inhibitor formation. Furthermore, this analysis showed that the risk of developing inhibitors increases when the variation causes a change of amino acid class. Conclusion: This study will help to correctly associate variations with inhibitor development and aid in early characterization of novel variants.
引用
收藏
页码:77 / 83
页数:7
相关论文
共 38 条
[1]   Genetic risk factors for inhibitors in haemophilia A [J].
Bardi, Edit ;
Astermark, Jan .
EUROPEAN JOURNAL OF HAEMATOLOGY, 2015, 94 :7-10
[2]   Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A [J].
Bogdanova, Nadja ;
Markoff, Arseni ;
Eisert, Roswith ;
Wermes, Cornelia ;
Pollmann, Hartmut ;
Todorova, Albena ;
Chlystun, Marcin ;
Nowak-Goettl, Ulrike ;
Horst, Juergen .
HUMAN MUTATION, 2007, 28 (01) :54-60
[3]   Normal thrombin generation [J].
Butenas, S ;
van't Veer, C ;
Mann, KG .
BLOOD, 1999, 94 (07) :2169-2178
[4]   The role of previously untreated patient studies in understanding the development of FVIII inhibitors [J].
Carcao, M. ;
Re, W. ;
Ewenstein, B. .
HAEMOPHILIA, 2016, 22 (01) :22-31
[5]   Reactivity profile of anti-factor VIII antibodies with designed synthetic peptides mimicking epitopes of the C2 and a1 domains [J].
Chaves, D. G. ;
Velloso-Rodrigues, C. ;
Moreau, V. ;
Nguyen, C. ;
Villard, S. ;
Belisario, A. R. ;
Granier, C. ;
Santoro, M. M. .
BRITISH JOURNAL OF HAEMATOLOGY, 2008, 141 (05) :708-715
[6]   Multiple sequence alignment with the Clustal series of programs [J].
Chenna, R ;
Sugawara, H ;
Koike, T ;
Lopez, R ;
Gibson, TJ ;
Higgins, DG ;
Thompson, JD .
NUCLEIC ACIDS RESEARCH, 2003, 31 (13) :3497-3500
[7]   In Silico profiling of deleterious amino acid substitutions of potential pathological importance in haemophlia A and haemophlia B [J].
Doss, George Priya C. .
JOURNAL OF BIOMEDICAL SCIENCE, 2012, 19
[8]  
FULCHER CA, 1987, BLOOD, V69, P1475
[9]   Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients [J].
Gorski, Marcin M. ;
Blighe, Kevin ;
Lotta, Luca A. ;
Pappalardo, Emanuela ;
Garagiola, Isabella ;
Mancini, Ilaria ;
Mancuso, Maria Elisa ;
Fasulo, Maria Rosaria ;
Santagostino, Elena ;
Peyvandi, Flora .
BLOOD, 2016, 127 (23) :2924-2933
[10]   Factor VIII Products and Inhibitor Development in Severe Hemophilia A [J].
Gouw, Samantha C. ;
van der Bom, Johanna G. ;
Ljung, Rolf ;
Escuriola, Carmen ;
Cid, Ana R. ;
Claeyssens-Donadel, Segolene ;
van Geet, Christel ;
Kenet, Gili ;
Makipernaa, Anne ;
Molinari, Angelo Claudio ;
Muntean, Wolfgang ;
Kobelt, Rainer ;
Rivard, George ;
Santagostino, Elena ;
Thomas, Angela ;
van den Berg, H. Marijke .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (03) :231-239