Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenemia.
OBJECTIVE
Congenital afibrinogenemia is a rare coagulation disorder whose molecular basis is still poorly characterized. Most mutations have been identified in the fibrinogen Aalpha- and gamma-chain genes, whereas only two missense mutations have been reported in the Bbeta-chain gene. The aim of this work was to widen knowledge about the mutational spectrum of this disease by analyzing the molecular bases of congenital afibrinogenemia in three unrelated Iranian patients.


METHODS
All patients showed unmeasurable levels of clottable fibrinogen in plasma. Mutational screening was performed by sequencing the whole coding region, including exon-intron boundaries and part of the promoter region of the three fibrinogen genes.


RESULTS
Sequencing in one patient revealed the presence of a novel nonsense mutation (3282C-->T) in exon 2 of the fibrinogen Bbeta-chain gene, causing a severe truncation of the corresponding polypeptide (R17X). In the remaining probands, two already known small deletions (4209delA and 4220delT), both located in exon 5 of the fibrinogen Aalpha-chain gene, were identified, and their effect at the protein level explored by computer-assisted analysis.


CONCLUSIONS
The identification of the first truncating mutation in the fibrinogen Bbeta-chain gene confirms the involvement of all three fibrinogen genes in the pathogenesis of congenital afibrinogenemia and widens the mutational spectrum of the disease. This knowledge is clinically essential in order to carry out prenatal diagnosis in families at risk.
Asselta
Rosanna
R
Department of Biology and Genetics for Medical Sciences, University of Milan, via Viotti 3/5, 20133 Milan, Italy.
Spena
Silvia
S
Duga
Stefano
S
Peyvandi
Flora
F
Malcovati
Massimo
M
Mannucci
Pier Mannuccio
PM
Tenchini
Maria Luisa
ML
D000293:Adolescent; D000347:Afibrinogenemia / Q000208:ethnology / Q000235:genetics*; D000595:Amino Acid Sequence; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D007438:Introns / Q000235:genetics; D007492:Iran; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017384:Sequence Deletion
C115499:BBeta fibrinogen; D018389:Codon, Nonsense; C464794:fibrinogen Aalpha; D005340:Fibrinogen