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

Abstract

AbstractThe 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.