Abstract
Factor IX (encoded by F9) is a protein in the coagulation process, where its lack or deficiency leads to hemophilia B. This condition has been much less studied than hemophilia A, especially in Latin America. We analyzed the structural and functional impact of 54 missense mutations (18 reported by us previously, and 36 other mutations from the Factor IX database) through molecular modeling approaches. To accomplish this task, we examine the electrostatic patterns, hydrophobicity/hydrophilicity, disulfide, and H-bond differences of the Factor IX structures harboring the missense mutations found, correlating them with their clinical effects. The 54 mutated sequences were modeled and their physicochemical features were determined and used as input in clusterization tools. The electrostatic pattern seems to influence in disease severity, especially for mutations investigated in epidermal growth factors 1 and 2 (EGF1/2) domains. The combined use of all physicochemical information improved the clustering of structures associated to similar phenotypes, especially for mutations from GLA and EGF1-2 domains. The effect of mutations in the disease phenotype severity seems to be a complex interplay of molecular features, each one contribut...Continue Reading
References
Aug 1, 1993·British Journal of Haematology·M TartaryJ M Lavergne
Aug 1, 1993·Human Molecular Genetics·E VielhaberS S Sommer
Jan 1, 1995·Human Mutation·K WulffF H Herrmann
Jan 20, 1998·Trends in Biochemical Sciences·R A LaskowskiJ M Thornton
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Dec 29, 1999·Human Mutation·A R Jaloma-CruzS S Sommer
Jan 27, 2000·Human Genetics·R P KetterlingS S Sommer
Jun 30, 2000·Human Mutation·J Z LiuS S Sommer
Oct 3, 2000·Human Mutation·X LiS S Sommer
Jan 30, 2003·Trends in Cardiovascular Medicine·Amy E Schmidt, S Paul Bajaj
Aug 28, 2003·Journal of Thrombosis and Haemostasis : JTH·G JayandharanA Srivastava
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 14, 2004·Haemophilia : the Official Journal of the World Federation of Hemophilia·S SchulmanR Wallensten
Dec 1, 2004·Haemophilia : the Official Journal of the World Federation of Hemophilia·M S EnayatF G H Hill
Apr 6, 2006·Bioinformatics·Ryota Suzuki, Hidetoshi Shimodaira
Sep 8, 2006·BMC Bioinformatics·Chris J NeedhamDavid R Westhead
Apr 19, 2008·Nucleic Acids Research·Stefan RichterRebecca C Wade
Jul 16, 2008·Haemophilia : the Official Journal of the World Federation of Hemophilia·M-J KwonS-H Kim
Mar 6, 2009·Journal of Pediatric Hematology/oncology·Leera QuadrosShrimati Shetty
Dec 2, 2010·Haemophilia : the Official Journal of the World Federation of Hemophilia·H ElmahmoudiE Gouider
Apr 26, 2011·Molecular Immunology·Dinler A AntunesGustavo F Vieira
Nov 23, 2011·Haemophilia : the Official Journal of the World Federation of Hemophilia·C H MillerUNKNOWN Hemophilia Inhibitor Research Study Investigators
Apr 26, 2012·Bioinformatics·Nicholas SmithEmil Alexov
Apr 27, 2013·Journal of Thrombosis and Haemostasis : JTH·P M RallapalliS J Perkins
Apr 27, 2013·Nucleic Acids Research·Liam J McGuffinDaniel B Roche
Feb 26, 2014·Proteome Science·Mina MalekiLuis Rueda
May 8, 2015·Nature Protocols·Lawrence A KelleyMichael J E Sternberg
Jul 5, 2015·Molecular Immunology·Marcus F A MendesGustavo F Vieira
Dec 13, 2016·Scientific Reports·Maryam KarimiMichael J Davies
Jul 20, 2017·Haemophilia : the Official Journal of the World Federation of Hemophilia·M R MeirelesE Bandinelli