Afibrinogenemia in a compound heterozygote: making sense out of missense

Congenital afibrinogenemia is an autosomal recessive disorder characterized by the absence of fibrinogen from the circulation. It had long been anticipated that the basis for this disorder would be rooted in a homozygous defect in one or another of the fibrinogen α, β, and γ genes: FGA, FGB, and FGG. Indeed, the first reported genetic analysis of an afibrinogenemic subject by Neerman-Arbez et al¹  showed a homozygous 11-kb deletion in FGA. Since then, numerous homozygous fibrinogen gene mutations involving each of the genes have been described, and all but a few are null mutations (frameshift, nonsense, or splice-site). However, the report in this issue by Vu and colleagues (page 4413) shows that afibrinogenemia also occurred in a subject displaying compound heterozygosity of FGB. Their descriptive analysis has provided new insights into the pathogenesis of this disorder.

There are 6 fibrinogen gene mutations in afibrinogenemic or hypofibrinogenemic subjects that involve missense mutations of FGB, and they occur in a segment of the gene that corresponds to the C-terminal portion of the fibrinogen Bβ chain. Parenthetically, this region is highly conserved among vertebrates. In 2 cases of afibrinogenemia, expression of the defective gene coupled with studies of intracellular or secreted hexameric fibrinogen showed that assembly to hexamers occurred but that secretion was deficient.²  In a heterozygote manifesting hypofibrinogenemia, a mutation in the FBG region resulted in truncation at Bβ440.³  In another such family, an FGB mutation 3 codons upstream (W467X) also resulted in Bβ chain truncation and nonsecretion.⁴  In the present report by Vu et al, an afibrinogenemic subject was found to have compound heterozygous mutations of FGB. Each of the heterozygous parents was hypofibrinogenemic. One of the FGB mutations was a previously described nonsense mutation in the N-terminal coding region that led to severe Bβ chain truncation.⁵  The second FGB mutation involved a missense mutation in the C-terminal coding region leading to a G444S substitution. Coexpression of the G444S mutant plus wild-type Bβ chains in combination with normal FGA and FGG showed that an assembled fibrinogen hexamer was still secreted. In contrast, coexpression of normal fibrinogen with the mutant G444S FGB alone eliminated secretion, thereby providing a coherent explanation for afibrinogenemia in the compound heterozygotic state. As a finale to this discussion of missense, a recently reported heterozygous FGB mutation, R285H, resulted in hypofibrinogenemia.⁶  As emphasized by Vu et al, such mutations in the C-terminal coding region of FGB confirm the importance of an intact C-terminal Bβ chain for successful fibrinogen secretion.