Pg. Gallagher et al., RECURRENT FATAL HYDROPS-FETALIS ASSOCIATED WITH A NUCLEOTIDE SUBSTITUTION IN THE ERYTHROCYTE BETA-SPECTRIN GENE, The Journal of clinical investigation, 95(3), 1995, pp. 1174-1182
We studied a kindred in which four third-trimester fetal losses occurr
ed, associated with severe Coombs-negative hemolytic anemia and hydrop
s fetalis. Postmortem examination of two infants revealed extensive ex
tramedullary erythropoiesis. Studies of erythrocytes and erythrocyte m
embranes from the parents revealed abnormal erythrocyte membrane mecha
nical stability as well as structural and functional abnormalities in
spectrin, the principal structural protein of the erythrocyte membrane
. Genetic studies identified a point mutation of the beta-spectrin gen
e, S2019P, in a region of beta spectrin that is critical for normal sp
ectrin function. Both parents and two living children were heterozygou
s for this mutation; three infants dying of hydrops fetalis were homoz
ygous for this mutation. In an in vitro assay using recombinant peptid
es, the mutant beta-spectrin peptide demonstrated a significant abnorm
ality in its ability to interact with alpha spectrin. This is the firs
t description of a molecular defect of the erythrocyte membrane associ
ated with hydrops fetalis.