Recurrent fatal hydrops fetalis associated with a nucleotide substitution in the erythrocyte beta-spectrin gene.

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.

[1]  J. Morrow,et al.  A partial structural repeat forms the heterodimer self-association site of all beta-spectrins. , 1994, The Journal of biological chemistry.

[2]  D. Branton,et al.  Crystal structure of the repetitive segments of spectrin. , 1993, Science.

[3]  C. Birkenmeier,et al.  Complete nucleotide sequence of the murine erythroid beta-spectrin cDNA and tissue-specific expression in normal and jaundiced mice. , 1993, Blood.

[4]  A. Chishti,et al.  Spectrin cagliari. an Ala-->Gly substitution in helix 1 of beta spectrin repeat 17 that severely disrupts the structure and self-association of the erythrocyte spectrin heterodimer. , 1993, The Journal of biological chemistry.

[5]  B. Forget,et al.  The exon-intron organization of the human erythroid beta-spectrin gene. , 1993, Genomics.

[6]  D. Speicher,et al.  Location of the human red cell spectrin tetramer binding site and detection of a related "closed" hairpin loop dimer using proteolytic footprinting. , 1993, The Journal of biological chemistry.

[7]  M. Gilmore,et al.  Nucleotide sequence of a cDNA for canine beta-spectrin reveals high evolutionary conservation. , 1993, Biochimica et biophysica acta.

[8]  M. Watanabe,et al.  Characterization of human brain cDNA encoding the general isoform of beta-spectrin. , 1992, The Journal of biological chemistry.

[9]  K. Sahr,et al.  Mutations of the red blood cell membrane proteins: from clinical evaluation to detection of the underlying genetic defect. , 1992, Blood.

[10]  S. Warsof,et al.  Antenatal Classification of Hydrops Fetalis , 1992, Obstetrics and gynecology.

[11]  P. Boivin,et al.  Elliptocytosis‐associated spectrin Rouen (β220/218) has a truncated but still phosphorylatable β chain , 1992 .

[12]  B. Forget,et al.  Ankyrin binds to the 15th repetitive unit of erythroid and nonerythroid beta-spectrin , 1991, The Journal of cell biology.

[13]  F. Costa,et al.  A splice site mutation of the beta-spectrin gene causing exon skipping in hereditary elliptocytosis associated with a truncated beta-spectrin chain. , 1991, The Journal of biological chemistry.

[14]  F. Galibert,et al.  Spectrin Rouen (beta 220-218), a novel shortened beta-chain variant in a kindred with hereditary elliptocytosis. Characterization of the molecular defect as exon skipping due to a splice site mutation. , 1991, The Journal of clinical investigation.

[15]  J. Prchal,et al.  Molecular defect of truncated beta-spectrin associated with hereditary elliptocytosis. Beta-spectrin Gottingen. , 1991, The Journal of biological chemistry.

[16]  J. Lawler,et al.  Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. , 1990, Blood.

[17]  Y. Gillerot,et al.  Nonimmune hydrops fetalis associated with genetic abnormalities. , 1990, Obstetrics and gynecology.

[18]  A. Pekrun,et al.  Disorders of the red-cell membrane , 1990 .

[19]  M. P. S. Mier,et al.  Nonimmunologic hydrops fetalis: an etiopathogenetic approach through the postmortem study of 59 patients. , 1990, American journal of medical genetics.

[20]  P. Agre,et al.  Sequence and exon-intron organization of the DNA encoding the alpha I domain of human spectrin. Application to the study of mutations causing hereditary elliptocytosis. , 1989, The Journal of clinical investigation.

[21]  B. Harlow,et al.  Sonographic Evaluation of Hydrops Fetalis , 1989, Obstetrics and gynecology.

[22]  D. Smith,et al.  Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. , 1988, Gene.

[23]  N. Mohandas,et al.  Hereditary poikilocytic anemia associated with the co-inheritance of two alpha spectrin abnormalities. , 1988, Blood.

[24]  J. Lawler,et al.  Partial ankyrin and spectrin deficiency in severe, atypical hereditary spherocytosis. , 1988, The New England journal of medicine.

[25]  D. Speicher,et al.  Mutant forms of spectrin alpha-subunits in hereditary elliptocytosis. , 1987, The Journal of clinical investigation.

[26]  N. Mohandas,et al.  Unique alpha-spectrin mutant in a kindred with common hereditary elliptocytosis. , 1987, The Journal of clinical investigation.

[27]  Vann Bennett,et al.  Partial deficiency of erythrocyte spectrin in hereditary spherocytosis , 1985, Nature.

[28]  Vincent T. Marchesi,et al.  Erythrocyte spectrin is comprised of many homologous triple helical segments , 1984, Nature.

[29]  D. Fortune,et al.  Non‐immune hydrops fetalis: changing contribution to perinatal mortality , 1983, British journal of obstetrics and gynaecology.

[30]  J. Delaunay,et al.  Spectrin beta-chain variant associated with hereditary elliptocytosis. , 1982, The Journal of clinical investigation.

[31]  D. Speicher,et al.  A structural model of human erythrocyte spectrin. Alignment of chemical and functional domains. , 1982, The Journal of biological chemistry.

[32]  P. Agre,et al.  Deficient red-cell spectrin in severe, recessively inherited spherocytosis. , 1982, The New England journal of medicine.

[33]  J. Prchal,et al.  Defective spectrin dimer-dimer association with hereditary elliptocytosis. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[34]  V. Yu,et al.  Nonimmunologic Hydrops Fetalis: A Review of 61 Cases , 1982, Obstetrics and gynecology.

[35]  D. Speicher,et al.  Identification of functional domains of human erythrocyte spectrin. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Speicher,et al.  Identification of proteolytically resistant domains of human erythrocyte spectrin. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[37]  E. Ungewickell,et al.  Self-association of human spectrin. A thermodynamic and kinetic study. , 1978, European journal of biochemistry.

[38]  D. Wallach,et al.  Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane. , 1971, Biochemistry.

[39]  J. Delaunay,et al.  Mutations involving the spectrin heterodimer contact site: clinical expression and alterations in specific function. , 1993, Seminars in hematology.

[40]  C. F. Whitfield,et al.  Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis. , 1991, Blood.

[41]  T. Koyanagi,et al.  Intrauterine treatment of idiopathic hydrops fetalis , 1988, Journal of perinatal medicine.

[42]  C. Féo,et al.  Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases. , 1986, Nouvelle revue francaise d'hematologie.

[43]  V. Marchesi,et al.  Abnormal spectrin in hereditary elliptocytosis. , 1986, Blood.

[44]  N. Mohandas,et al.  A technique to detect reduced mechanical stability of red cell membranes: relevance to elliptocytic disorders. , 1982, Blood.