Spectrin Cosenza: a novel β chain variant associated with Sp αI/74 hereditary elliptocytosis

Qualtieri, Antonio; Pasqua, Angela Aurora; Bisconte, Maria Grazia; Pera, M. Le; Brancati, C.

doi:10.1046/j.1365-2141.1997.572703.x

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…The most common mutations causing HE involve the α-spectrin heterodimer self-association site [2,11]. However, variants in the β-spectrin gene (SPTB) have been found, including a mutation in a large German family with autosomal dominant HE [12], a family in Southern Italy with a C-to-G substitution at position 6284 of the SPTB gene [13], and two unrelated families from Sardinia [14]. …”

Section: Discussionmentioning

confidence: 99%

Variations in Both α-Spectrin (SPTA1) and β-Spectrin (SPTB) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis

et al. 2013

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We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis. Analysis of the α-spectrin gene (SPTA1) in the proband revealed two previously reported low-frequency heterozygous polymorphisms of unknown clinical significance and the α^LELY allele. In addition, a novel heterozygous mutation was identified in exon 2 of the β-spectrin gene SPTB. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2).

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Section: Discussionmentioning

confidence: 99%

Variations in Both α-Spectrin (SPTA1) and β-Spectrin (SPTB) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis

et al. 2013

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“…Splice site mutations in spectrins Göttingen, LePuy and Rouen and a nonsense mutation in spectrin Nagoya result in truncated β spectrin peptides defective in heterodimer self‐association (Maillet et al , 1996). Missense mutations in β spectrin are present in spectrins Buffalo, Cagliari, Cosenza, Cotonou, Kayes, Linguere, Paris and Providence, in which amino acid substitutions either disrupt the triple helical coiled‐coil structure that forms the spectrin dimer self‐association site or affect residues critical to the interaction (Tse et al , 1990; Sahr et al , 1993; Parquet et al , 1994; Gallagher et al , 1995, 1997; Glele‐Kakai et al , 1996; Qualtieri et al , 1997; Nicolas et al , 1998). Without exception, these mutations directly affect the heterodimer self‐association site of β spectrin (Fig 2).…”

Section: Hereditary Elliptocytosis and Hereditary Pyropoikilocytosis mentioning

confidence: 99%

Red blood cell membrane disorders

1999

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The red blood cell membrane is a multi-component structure that is responsible for many of the physiological functions and mechanical properties of the cell. Defects in any of these components can manifest as clinical disorders involving the erythrocytes. In the past few years there have been major advances in our understanding of the molecular basis of these disorders, in which mutational analysis has clarified many questions about the structure-function relationship of components of the red cell membrane. Some of these recent findings will be the subject of this review. A detailed discussion of the structure of the red cell membrane and the pathophysiology and clinical aspects of its disorders can be found in several recent reviews

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“…[25][26][27] This was followed by identification of numerous missense mutations located within the putative hybrid ␣-␤ repeat tetramer binding site that impaired tetramer formation and destabilized red cell membranes. 14,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Attempts to correlate spectrin mutations with clinical severity have been confounded by marked clinical, biochemical, and genetic variability. For instance, the same tetramer site missense mutation has been linked to asymptomatic HE, chronic hemolytic HE, and severe HPP phenotypes in cases where patients spanning multiple generations in larger families were studied.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site

Gaetani

Mootien

Harper

et al. 2008

Blood

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The most common hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) mutations are ␣-spectrin missense mutations in the dimer-tetramer self-association site. In this study, we systematically compared structural and functional properties of the 14 known HE/HPP mutations located in the ␣-spectrin tetramer binding site. All mutant ␣-spectrin recombinant peptides were well folded, stable structures, with only the R34W mutant exhibiting a slight structural destabilization. In contrast, binding affinities measured by isothermal titration calorimetry were greatly variable, ranging from no detectable binding observed for I24S, R28C, R28H, R28S, and R45S to approximately wild-type binding for R34W and K48R. Binding affinities for the other 7 mutants were reduced by approximately 10-to 100-fold relative to wild-type binding. Some sites, such as R28, were hot spots that were very sensitive to even relatively conservative substitutions, whereas other sites were only moderately perturbed by nonconservative substitutions. The R34W and K48R mutations were particularly intriguing mutations that apparently either destabilize tetramers through mechanisms not probed by the univalent tetramer binding assay or represent polymorphisms rather than the pathogenic mutations responsible for observed clinical symptoms. All ␣0 HE/HPP mutations studied here appear to exert their destabilizing effects through molecular recognition rather than structural mechanisms. IntroductionThe hereditary elliptocytosis (HE) syndromes are a common group of disorders characterized by elliptical erythrocytes on peripheral blood smear. [1][2][3][4] These disorders are characterized by marked clinical, biochemical, and genetic heterogeneity. Most patients with typical HE are asymptomatic, but others have chronic hemolysis or the related disorder hereditary pyropoikilocytosis (HPP). Biochemical and genetic heterogeneity is related to qualitative and/or quantitative defects in one of several erythrocyte membrane skeleton proteins, particularly ␣-spectrin, ␤-spectrin, protein 4.1R, or glycophorin C, which leads to mechanical weakness or fragility of the erythrocyte membrane skeleton.The majority of HE-associated defects occur in spectrin, the principal structural component of the red cell membrane skeleton. Spectrin is a flexible, rope-like molecule formed by antiparallel lateral association of 2 subunits, ␣-and ␤-spectrin, which are primarily composed of many tandem, homologous 106 amino acid motifs, or "spectrin type repeats." [5][6][7] Spectrin repeats are highly stable, independently folding 3 helix bundle units that are responsible for imparting much of the strength and flexibility to the erythrocyte membrane skeleton. For example, when conformational changes of membrane skeleton components are probed in intact red cells using cysteine-specific reagents, spectrin is the only membrane skeleton component showing stress-related increases in labeling indicative of tensile stress-related unfolding of specific domains. 8 Assembly of spectrin he...

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Spectrin Cosenza: a novel β chain variant associated with Sp α^I/74 hereditary elliptocytosis

Cited by 6 publications

References 16 publications

Variations in Both α-Spectrin <b><i>(SPTA1)</i></b> and β-Spectrin (<b><i>SPTB</i></b>) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis

Variations in Both α-Spectrin <b><i>(SPTA1)</i></b> and β-Spectrin (<b><i>SPTB</i></b>) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis

Red blood cell membrane disorders

Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site

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