The origins of hypofibrinogenemia in families with afibrinogenemia-causing mutations are poorly understood. Such mutations result in a number of effects known to date. Among these are splicing failure, no synthesis or no incorporation of abnormal peptide chains into the hexamer (Neerman-Arbez et al, Hum Genet. 2001;108:237240), and failure of hexamer secretion (Duga et al, Blood. 2000;95:1336-1341). In this issue, Neerman-Arbez and colleagues (page 3492) describe deletion of 25 amino acid residues from the carboxy terminal end of the Bβ chain that resulted in secretion failure. Affected were 2 children who were homozygous and afibrinogenemic and their parents from a consanguineous marriage who were heterozygous and hypofibrinogenemic. Also shown heterozygous was the 16-week fetus of an ongoing gestation, by using cells from amniocentesis. COS cells transfected with the mutant gene produced Bβ chains that were assembled into hexamers but were not secreted. This accounted for the absence of abnormal fibrinogen in the parents' plasma, and likely in plasma of heterozygous probands with other Bβ gene defects (Duga et al, Blood. 2000;95:1336-1341; Homer et al, Thromb Haemost. 2002;88:427-431) that in homozygous probands caused afibrinogenemia.
In experimental reports, deleted long Bβ segments (eg, Bβ 208-461) did not prevent secretion. Thus, secretion failure resulting from (a) much shorter (eg, 22 and 25 residue) carboxy terminal deletions and (b) single amino acid substitutions (Duga et al; Homer et al) is likely to reflect peptide folding differences as suggested (Duga et al). The unimpaired hexamer assembly implies that an intracellular compensatory response does not occur. If so, this can explain the hypofibrinogenemia and the functionally normal fibrinogen in the heterozygous state of these defects (Duga et al; Homer et al). It may also explain such a normal phenotype in other hypofibrinogenemic families with differing mutations, whether these are splicing defects and/or yet-to-be-discovered others. By extending their investigation to prenatal diagnosis and thus determining the zygosity of the mutation in the fetus, Neerman-Arbez et al underscored the potential clinical relevance of elucidating such defects.
