title: Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function.
abstract: BACKGROUND
  Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer.
  
  
  METHODS
  We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations.
  
  
  RESULTS
  All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation.
  
  
  CONCLUSIONS
  The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53127 Bonn, Germany. vytautas.ivaskevicius@ukb.uni-bonn.de
authors.forename: Vytautas
authors.initials: V
authors.lastname: Ivaskevicius
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.forename: Carville
authors.initials: C
authors.lastname: Bevans
authors.forename: Verena
authors.initials: V
authors.lastname: Schroeder
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Kohler
authors.forename: Hannelore
authors.initials: H
authors.lastname: Rott
authors.forename: Susan
authors.initials: S
authors.lastname: Halimeh
authors.forename: Petro E
authors.initials: PE
authors.lastname: Petrides
authors.forename: Harald
authors.initials: H
authors.lastname: Lenk
authors.forename: Manuele
authors.initials: M
authors.lastname: Krause
authors.forename: Bruno
authors.initials: B
authors.lastname: Miterski
authors.forename: Ursula
authors.initials: U
authors.lastname: Harbrecht
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D018360:Crystallography, X-Ray; D005177:Factor XIII Deficiency / Q000175:diagnosis / Q000235:genetics*; D026122:Factor XIIIa / Q000737:chemistry* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary / Q000235:genetics; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D026122:Factor XIIIa