Molecular Defect of Spectrin in the Family of a Child with Congenital Hemolytic Poikilocytic Anemia

Dhermy, Didier; Lecomte, Marie‐Christine; Garbarz, M; Féo, C; Gautero, H; Bournier, Odile; Galand, C; Herrera, A.; GRETILLAT, F.; Boivin, Pierre

doi:10.1203/00006450-198418100-00019

Cited by 2 publications

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“…The HPP phenotype has been associated with homozygosity for an a-spectrin structural variant (e.g., patients 1 and 5) (27,51,52), as well as double heterozygosity for two different structural variants (36,41,(53)(54)(55). Other (43) to show the potential intrachain interaction between a spectrin helices.…”

Section: Resultsmentioning

confidence: 99%

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A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.

et al. 1992

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IntroductionWe studied nine individuals from five unrelated families with aI/46-50a hereditary elliptocytosis (HE) The erythrocyte membrane skeleton is a network of proteins on the inner surface of the red cell membrane that is responsible for maintaining the shape and deformability ofthe erythrocyte (1-3). The principal proteins ofthe erythrocyte membrane skeleton include spectrin, ankyrin, protein 4.1, and actin (4). The major component of the erythrocyte membrane skeleton, spectrin, is composed oftwo structurally homologous but nonidentical proteins, a-and f3-spectrin. a-and j3-Spectrin intertwine to form heterodimers, which in turn self-associate in a head-to-head configuration to form tetramers and larger oligomers (5). These higher order tetramers and oligomers of spectrin appear to be critical for erythrocyte membrane stability as well as erythrocyte shape and function. Hemolytic anemias due to qualitative and quantitative defects in the erythrocyte membrane skeleton proteins, including spectrin, are an important group ofhereditary anemias. Hereditary elliptocytosis (HE)' and hereditary pyropoikilocytosis (HPP) are two of these disorders (for reviews, see references 6-9). HE, characterized by the presence of elliptically shaped erythrocytes in the peripheral blood, is a clinically heterogeneous group of disorders ranging from the asymptomatic carrier state to severe, symptomatic hemolytic anemia. HPP, as originally described by Zarkowsky et al. (10), is an uncommon, severe hemolytic anemia characterized by abnormal erythrocyte sensitivity to heat and erythrocyte morphology reminiscent of that seen in patients after a thermal burn. HE and HPP share a number ofbiochemical and molecular defects, particularly abnormalities in a spectrin (1 1-13).After limited digestion with trypsin and two-dimensional polyacrylamide gel electrophoresis, normal spectrin can be resolved into five a and four ,B proteolytically resistant domains (14,15

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Section: Resultsmentioning

confidence: 99%

“…Spectrin was extracted by incubating white ghosts overnight at 4VC in low ionic strength buffer (26). The content of spectrin dimers and tetramers was determined by nondenaturing gel electrophoresis as described (27,28).…”

Section: Methodsmentioning

confidence: 99%

A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.

et al. 1992

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Prenatal diagnosis of hereditary elliptocytosis with molecular defect of spectrin

et al. 1987

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Hereditary elliptocytosis (HE) is, in the heterozygous state, a common mild congenital hemolytic disease. In contrast, homozygous elliptocytosis is a severe transfusion-dependent hemolytic anemia. The major determinant of red cell membrane shape and stability is a two-dimensional proteinaceous meshwork named membrane skeleton. Spectrin, the most important protein of the membrane skeleton, is basically a heterodimer composed of alpha and beta chains. Within the membrane, spectrin dimers self-associate to form tetramers. In type I HE spectrin dimer self-association is defective and an excess of spectrin dimer is present in the patient's red cell membranes. The defective self-association is often correlated with an abnormality of the spectrin alpha chain which is depicted by limited tryptic digest of spectrin. In a family previously studied by us (Dhermy et al., 1984), the search for a spectrin defect in the red cells of the fetus of the pregnant mother was indicated for the following reasons: the diagnosis of heterozygous type I HE with the same spectrin variant had been made in the mother as well as in the father. Moreover, homozygous HE had been recognized in one of the children born two years previously with a persistent and severe transfusion dependent hemolytic anemia. Preliminary studies of normal fetal erythrocytes at twenty weeks gestation have shown that fetal and adult spectrin molecules are identical. The results obtained in the fetus at risk allowed us to diagnose type I HE (though elliptocytes were not present in the blood) for the following reasons: (i) erythrocyte deformability was decreased (ii) spectrin self-association was defective with an excess of dimer species in the membrane (iii) limited tryptic digest of spectrin showed the same abnormal pattern as seen in the heterozygous mother, with a decrease in the 80,000-dalton peptide and a concomitant increase in the 74,000-dalton peptide. The heterozygous state, strongly suspected on the tryptic digest pattern of fetal spectrin, was confirmed when the mother gave birth to a baby who did not have hemolytic anemia during the first 18 months of life.

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Molecular Defect of Spectrin in the Family of a Child with Congenital Hemolytic Poikilocytic Anemia

Cited by 2 publications

References 10 publications

A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.

A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.

Prenatal diagnosis of hereditary elliptocytosis with molecular defect of spectrin

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