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

The molecular basis of a novel congenital afibrinogenemia has been determin ed. The proposita, the only affected member in a consanguineous Norwegian f amily, suffers from a moderate to severe bleeding disorder due to the total absence of any detectable fibrinogen. Dot blots of solubilized platelets r evealed a small amount of gamma chain but no A alpha or B beta chains, wher eas no chains were detected in plasma dot blots. DNA sequencing of the A al pha chain gene revealed a homozygous C-->T transversion 557 nucleotides fro m the transcription initiation site. This nucleotide change predicts the no nsense mutation A alpha 149 Arg (CGA)-->stop (TGA). Early truncation of the A alpha chain appears to result in defective assembly or secretion of fibr inogen, probably due to the removal of the C-terminal disulfide ring residu es that are critically required for the formation of a stable 3-chained hal f molecule.