Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion

Congenital afibrinogenemia is a rare autosomal recessive disorder character ized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Although several m utations in the fibrinogen genes associated with dysfibrinogenemia and hypo fibrinogenemia have been described, the genetic defects of congenital afibr inogenemia are largely unknown, except for a recently reported Il-kb deleti on of the fibrinogen A alpha-chain gene. Nevertheless, mutation mechanisms other than the deletion of a fibrinogen gene are likely to exist because pa tients with afibrinogenemia showing no gross alteration within the fibrinog en cluster have been reported. We tested this hypothesis by studying the af fected members of two families, one Italian and one Iranian, who had no evi dence of large deletions in the fibrinogen genes. Sequencing of the fibrino gen genes in the 2 probands detected 2 different homozygous missense mutati ons in exons 7 and 8 of the B beta-chain gene, leading to amino acid substi tutions Leu353Arg and Gly400Asp, respectively, transient transfection exper iments with plasmids expressing wildtype and mutant fibrinogens demonstrate d that the presence of either mutation was sufficient to abolish fibrinogen secretion. These findings demonstrated that missense mutations in the B be ta fibrinogen gene could cause congenital afibrinogenemia by impairing fibr inogen secretion. (C) 2000 by The American Society of Hematology.