title: Coagulation Factor XIIIA Subunit Missense Mutations Affect Structure and Function at the Various Steps of Factor XIII Action.
abstract: Inherited defects of coagulation Factor XIII (FXIII) can be categorized into severe and mild forms based on their genotype and phenotype. Heterozygous mutations occurring in F13A1 and F13B genes causing mild FXIII deficiency have been reported only in the last few years primarily because the mild FXIII deficiency patients are often asymptomatic unless exposed to some kind of a physical trauma. However, unlike mutations causing severe FXIII deficiency, many of these mutations have not been comprehensively characterized based on expression studies. In our current article, we have transiently expressed 16 previously reported missense mutations detected in the F13A1 gene of patients with mild FXIII deficiency and analyzed their respective expression phenotype. Complimentary to expression analysis, we have used in silico analysis to understand and explain some of the in vitro findings. The expression phenotype has been evaluated with a number of expression phenotype determining assays. We observe that the mutations influence different aspects of FXIII function and can be functionally categorized on the basis of their expression phenotype. We identified mutations which even in heterozygous form would have strong impact on the functional status of the protein (namely mutations p.Arg716Gly, p.Arg704Gln, p.Gln602Lys, p.Leu530Pro, p.His343Tyr, p.Pro290Arg, and p.Arg172Gln).
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany. arijit.biswas@ukb.uni-bonn.de.
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Paul Ehrlich Institut, Langen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Dodt
authors.affiliation: Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.affiliation: Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hethershaw
authors.affiliation: Nees Institute for Biodiversity of Plants, University of Bonn, Bonn, Germany.
authors.forename: Hans Juergen
authors.initials: HJ
authors.lastname: Ensikat
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: Vytautas
authors.initials: V
authors.lastname: Ivaskevicius
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany. johannes.oldenburg@ukb.uni-bonn.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D003198:Computer Simulation; D005177:Factor XIII Deficiency / Q000235:genetics*; D026122:Factor XIIIa / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D026122:Factor XIIIa; D013917:Thrombin
keywords: F13A1; F13B; Factor XIII(FXIII)deficiency; expression analysis; in silico structural analysis; molecular basis of inherited coagulopathies