Blood, 1 May 2003, Vol. 101, No. 9, pp. 3342-3342
Progress on the afibrinogenemia-hypofibrinogenemia link
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 B
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 B
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 B
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 B segments (eg, B 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.
Dennis K. Galanakis
SUNY at Stony
Brook
