Homozygous truncation of the fibrinogen Aα chain within the coiled coil causes congenital afibrinogenemia

• Published in: Blood Vol. 96; no. 2; pp. 773 - 775
• Main Authors: Fellowes, Andrew P., Brennan, Stephen O., Holme, Randi, Stormorken, Helge, Brosstad, Frank R., George, Peter M.
• Format: Journal Article
• Language: English
• Published: 15.07.2000
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.2.773.014k07_773_775

The molecular basis of a novel congenital afibrinogenemia has been determined. The proposita, the only affected member in a consanguineous Norwegian family, suffers from a moderate to severe bleeding disorder due to the total absence of any detectable fibrinogen. Dot blots of solubilized platelets revealed a small amount of γ chain but no A or Bβ chains, whereas no chains were detected in plasma dot blots. DNA sequencing of the A chain gene revealed a homozygous C→T transversion 557 nucleotides from the transcription initiation site. This nucleotide change predicts the nonsense mutation A 149 Arg (CGA)→stop (TGA). Early truncation of the A chain appears to result in defective assembly or secretion of fibrinogen, probably due to the removal of the C-terminal disulfide ring residues that are critically required for the formation of a stable 3-chained half molecule.