Sp alpha V/41: a common spectrin polymorphism at the alpha IV-alpha V domain junction. Relevance to the expression level of hereditary elliptocytosis due to alpha-spectrin variants located in trans.

Alloisio, Nicole; Morlé, Laurette; Maréchal, J; Roux, Antoine; Ducluzeau, MT; Guetarni, Djamel; Pothier, B; Baklouti, Faouzi; Ghanem, Abi; Kastally, R.; Delaunay, Jean

doi:10.1172/jci115250

Cited by 65 publications

(31 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hereditary pyropoikilocytosis has been described in a patient presenting a spαI/74 mutation associated in trans with the α LELY allele [27]. However, our study showed that the association of α LELY allele in trans with the spαI/50 L260P substitution did not lead to a pronounced worsening of clinical or laboratory features, although it may induce mild hemolysis.…”

Section: Discussioncontrasting

confidence: 64%

See 1 more Smart Citation

Expression of Spectrin αI/50 Hereditary Elliptocytosis and Its Association with the α<sup>LELY</sup> Allele

Bassères¹,

Pranke²,

Vicentim³

et al. 1998

Acta Haematol

View full text Add to dashboard Cite

Hereditary elliptocytosis (HE) is a group of hemolytic anemias characterized by the presence of elliptical erythrocytes. The underlying alterations lie in the proteins of the membrane skeleton. Defects of the αI domain of spectrin have been defined based on a decrease in the normal 80-kD αI domain and a concomitant increase in one or more lower molecular weight peptides. We have studied three Brazilian kindreds with black ancestry, who presented mild common spαI/50 HE. Our aim was to determine the molecular alteration responsible for the spαI/50 HE observed in these three kindreds and to evaluate the presence and influence of allele α^LELY in the expression of this type of HE. In order to establish the molecular defect, exons 5, 6 and 11 were amplified and submitted to a nonradioactive single strand conformation polymorphism protocol. An identical band shift in exon 6 was observed in all 3 patients and their affected relatives. Direct sequencing of the amplification products of exon 6 showed the same molecular defect in all patients: a T→C substitution, responsible for the L260P mutation. Allele α^LELY, detected by PCR and restriction enzyme digestion, was present in the heterozygous form in the three propositi and was associated in trans with the elliptocytogenic mutation. Blood smears of the patients with HE and α^LELY in trans showed pronounced elliptocytosis, poikilocytosis and a few small red cell fragments, whereas the blood smears of their relatives, who had HE without allele α^LELY, showed mild common HE with a predominance of ovalocytes and the absence of poikilocytes. We conclude that allele α^LELY does not lead to the worsening of clinical conditions when associated in trans with mild HE, but can be easily distinguished by a blood smear analysis. The predominance of the L260P mutation in the kindreds studied could be related to the colonization of Brazil during the slave trade by Africans from the Benin-Togo area, where this mutation is particularly common.

show abstract

Section: Discussioncontrasting

confidence: 64%

“…Probably, the mutation in exon 40 has no functional consequence, but causes an increase in the αV 41-kD fragment [27]. On the other hand, the mutation in intron 45 is responsible for the partial skipping of exon 46 during splicing [12].…”

Section: Discussionmentioning

confidence: 99%

Expression of Spectrin αI/50 Hereditary Elliptocytosis and Its Association with the α<sup>LELY</sup> Allele

Bassères¹,

Pranke²,

Vicentim³

et al. 1998

Acta Haematol

View full text Add to dashboard Cite

show abstract

“…This dual presentation evokes the involvement of some recurrent aggravating factor. The latter was found and coined allele α LELY [12, 13]. By itself, α LELY remains silent in both the heterozygous and the homozygous states (because of the large excess of α-chains normally synthesized).…”

Section: Hereditary Elliptocytosis and Hereditary Poikilocytosismentioning

confidence: 99%

Molecular Basis of Red Cell Membrane Disorders

Delaunay

2002

Acta Haematol

View full text Add to dashboard Cite

We will consider an array of genetic disorders of the red cell membrane. Some affect well-known genes. The mutations of most cases of hereditary spherocytosis (HS) are located in the following genes: ANK1, SPTB, SLC4A1, EPB42 and SPTA1, which encode ankyrin, spectrin β-chain, the anion exchanger 1 (band 3), protein 4.2 and spectrin α-chain, respectively. A dominant form of distal renal tubular acidosis also stems from distinct mutations in the SLC4A1 gene. The mutations responsible for hereditary elliptocytosis (HE) and its aggravated form, poikilocytosis (HP), lie in the SPTA1 and SPTB gene, already mentioned, and in the EPB41 gene encoding protein 4.1. Whereas in HS, the SPTA1 and SPTB gene mutations tend to abolish the synthesis of the corresponding chains, in HE/HP, they hinder spectrin tetramerization. Allele α^LELY is a common polymorphic allele which plays the role of an aggravating factor when it occurs in trans of an elliptocytogenic allele of the SPTA1 gene. Southeast Asian ovalocytosis results from a 27- nucleotide deletion in the SLC4A1 gene. Besides these conditions in which the mutations were reached from known alterations in the proteins, other conditions required a positional cloning approach. Such are the genetic disorders of membrane permeability to monovalent cations. Knowledge is the most advanced as regards dehydrated hereditary stomatocytois (DHS). DHS was shown to belong to a pleiotropic syndrome: DHS + fetal edema + pseudohyperkalemia, which maps to 16q23–24. Concerning DHS and another disease of the same class, overhydrated hereditary stomatocytosis, splenectomy almost certainly appears to elicit thromboembolic accidents.

show abstract

“…, that affects dimer assembly (Alloisio et al, 1991;Wilmotte et al, 1993;Randon et al, 1994). When this mutation is present along with an elliptocytosis mutation on the same chain, symptoms of the elliptocytosis mutation are often silent or mitigated since the ␣ LELY mutation will decrease incorporation of the mutated chain onto the membrane.…”

Section: Lelymentioning

confidence: 99%

Mapping the Human Erythrocyte β-Spectrin Dimer Initiation Site Using Recombinant Peptides and Correlation of Its Phasing with the α-Actinin Dimer Site

Ursitti¹,

Kotula²,

DeSilva

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human erythroid spectrin dimer assembly is initiated by the association of a specific region near the N-terminal of ␤-spectrin with a complementary region near the C-terminal of ␣-spectrin (Speicher, D. W., Weglarz, L., and DeSilva, T. M. (1992) J. Biol. Chem. 267, 14775-14782). Both spectrin subunits consist primarily of tandem, 106-residue long, homologous, triple-helical motifs. In this study, the minimal region of ␤-spectrin required for association with ␣-spectrin was determined using recombinant peptides. The start site (phasing) for construction of dimerization competent ␤-spectrin peptides was particularly critical. The beginning of the first homologous motif for both ␤-spectrin and the related dimerization site of ␣-actinin is approximately 8 residues earlier than most spectrin motifs. A four-motif ␤-spectrin peptide (␤1-4 ؉ ) with this earlier starting point bound to full-length ␣-spectrin with a K d of about 10 nM, while deletion of these first 8 residues reduced binding nearly 10-fold. N-and C-terminal truncations of one or more motifs from ␤1-4 ؉ showed that the first motif was essential for dimerization since its deletion abolished binding, but ␤1؉ alone could not associate with ␣-monomers. The first two motifs (␤1-2 ؉ ) represented the minimum lateral dimer assembly site with a K d of about 230 nM for interaction with full-length ␣-spectrin or an ␣-spectrin nucleation site recombinant peptide, ␣18 -21. Each additional motif increased the dimerization affinity by approximately 5-fold. In addition to this strong inter-subunit dimer association, interactions between the helices of a single triple-helical motif are frequently strong enough to maintain a noncovalent complex after internal protease cleavage similar to the interactions thought to be involved in tetramer formation. Analysis of hydrodynamic radii of recombinant peptides containing differing numbers of motifs showed that a single motif had a Stokes radius of 2.35 nm, while each additional motif added only 0.85 nm to the Stokes radius. This is the first direct demonstration that spectrin's flexibility arises from regions between each triple helical motif rather than from within the segment itself and suggests that current models of inter-motif connections may need to be revised.The membrane skeleton of the human erythrocyte consists of a network of proteins that associates with the inner surface of the cell membrane and imparts remarkable structural integrity and flexibility to circulating erythrocytes. Spectrin is the major structural component of this specialized submembranous protein network. The basic functional unit of spectrin is a heterodimer formed by side-to-side, antiparallel association of a 280-kDa ␣ subunit with a 246-kDa ␤ subunit. Spectrin dimers associate head-to-head to form tetramers, the predominant form of spectrin in the membrane skeleton. These tetramers cross-link short actin oligomers, an association modulated by band 4

show abstract

Sp alpha V/41: a common spectrin polymorphism at the alpha IV-alpha V domain junction. Relevance to the expression level of hereditary elliptocytosis due to alpha-spectrin variants located in trans.

Cited by 65 publications

References 23 publications

Expression of Spectrin αI/50 Hereditary Elliptocytosis and Its Association with the α<sup>LELY</sup> Allele

Expression of Spectrin αI/50 Hereditary Elliptocytosis and Its Association with the α<sup>LELY</sup> Allele

Molecular Basis of Red Cell Membrane Disorders

Mapping the Human Erythrocyte β-Spectrin Dimer Initiation Site Using Recombinant Peptides and Correlation of Its Phasing with the α-Actinin Dimer Site

Contact Info

Product

Resources

About