The molecular mechanisms of congenital hypofibrinogenaemia.

Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes (α, β and γ). However, it does not usually result in a clinically significant condition unless inherited in a homozygous or compound heterozygous state, where it results in a severe bleeding disorder, afibrinogenaemia. Various protein and expression studies have improved our understanding of how mutations causing hypo- and afibrinogenaemia affect secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations can perturb chain assembly as in the γ153 Cys → Arg case, while others such as the Bβ Leu → Arg and the Bβ414 Gly → Ser mutations allow intracellular hexamer assembly but inhibit protein secretion. An interesting group of mutations, such as γ284 Gly → Arg and γ375 Arg → Trp, not only cause hypofibrinogenaemia but are also associated with liver disease. The nonexpression of these variant chains in plasma fibrinogen is due to retention in the endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.