title: Recurrent fatal hydrops fetalis associated with a nucleotide substitution in the erythrocyte beta-spectrin gene.
abstract: We studied a kindred in which four third-trimester fetal losses occurred, associated with severe Coombs-negative hemolytic anemia and hydrops fetalis. Postmortem examination of two infants revealed extensive extramedullary erythropoiesis. Studies of erythrocytes and erythrocyte membranes from the parents revealed abnormal erythrocyte membrane mechanical 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 gene, S2019P, in a region of beta spectrin that is critical for normal spectrin function. Both parents and two living children were heterozygous for this mutation; three infants dying of hydrops fetalis were homozygous for this mutation. In an in vitro assay using recombinant peptides, the mutant beta-spectrin peptide demonstrated a significant abnormality in its ability to interact with alpha spectrin. This is the first description of a molecular defect of the erythrocyte membrane associated with hydrops fetalis.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06437.
authors.forename: P G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: S A
authors.initials: SA
authors.lastname: Weed
authors.forename: W T
authors.initials: WT
authors.lastname: Tse
authors.forename: L
authors.initials: L
authors.lastname: Benoit
authors.forename: J S
authors.initials: JS
authors.lastname: Morrow
authors.forename: S L
authors.initials: SL
authors.lastname: Marchesi
authors.forename: N
authors.initials: N
authors.lastname: Mohandas
authors.forename: B G
authors.initials: BG
authors.lastname: Forget
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000235:genetics*; D004913:Erythrocytes, Abnormal; D005260:Female; D005313:Fetal Death; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics* / Q000401:mortality; D007812:Laos / Q000208:ethnology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008969:Molecular Sequence Data; D010375:Pedigree; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D013049:Spectrin / Q000235:genetics* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D010446:Peptide Fragments; D013049:Spectrin; D014357:Trypsin