title: Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function.
abstract: Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany, arijit.biswas@ukb.uni-bonn.de.
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.forename: Vytautas
authors.initials: V
authors.lastname: Ivaskevicius
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: Varvenne
authors.forename: Brigitte
authors.initials: B
authors.lastname: Brand
authors.forename: Hannelore
authors.initials: H
authors.lastname: Rott
authors.forename: Iris
authors.initials: I
authors.lastname: Haussels
authors.forename: Heiko
authors.initials: H
authors.lastname: Ruehl
authors.forename: Ute
authors.initials: U
authors.lastname: Scholz
authors.forename: Robert
authors.initials: R
authors.lastname: Klamroth
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D003198:Computer Simulation; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics*; D005177:Factor XIII Deficiency / Q000235:genetics*; D005260:Female; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010455:Peptides / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D021122:Protein Subunits / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D055815:Young Adult
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D021122:Protein Subunits; C061895:factor XIII activation peptide; C064015:factor XIII subunit A; D005176:Factor XIII