title: In vitro secretion deficits are common among human coagulation factor XIII subunit B missense mutants: correlations with patient phenotypes and molecular models.
abstract: Coagulation factor XIII (FXIII) proenzyme circulates in plasma as a heterotetramer composed of two each of A and B subunits. Upon activation, the B subunits dissociate from the A subunit dimer, which gains transglutaminase activity to cross-link preformed fibrin clots increasing mechanical strength and resistance to degradation. The B subunits are thought to possess a carrier/protective function before FXIII activation. Mutations in either A or B subunits are associated with pathological patient phenotypes characterized by mild to severe bleeding. In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied. To investigate the likely molecular environments of the missense residues, we created molecular models of individual FXIIIB Sushi domains using phylogenetically similar complement factor H Sushi domain structural templates. Assessment of the local molecular environments for the models suggested surface or buried positions for each mutant residue and possible pathological mechanisms. The in vitro expression system and in silico analytical methods and models we developed can be used to further investigate the molecular basis of FXIIIB mutation pathologies.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Carville G
authors.initials: CG
authors.lastname: Bevans
authors.forename: Vytautas
authors.initials: V
authors.lastname: Ivaskevicius
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D002460:Cell Line; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
chemical_list: D005176:Factor XIII; C054380:factor XIIIb
keywords: F13B; FXIIIB; expression analysis; factor XIII deficiency; homology modeling