Low expression allele alpha LELY of red cell spectrin is associated with mutations in exon 40 (alpha V/41 polymorphism) and intron 45 and with partial skipping of exon 46.

Wilmotte, R; Maréchal, J; Morlé, Laurette; Baklouti, Faouzi; Philippe, N; Kastally, R.; Kotula, Leszek; Delaunay, Jean; Alloisio, Nicole

doi:10.1172/jci116432

Cited by 101 publications

(81 citation statements)

References 29 publications

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“…The coinheritance of a mutated and of a weakly expressed "normal" allele has previously been reported in hereditary spherocytosis 23 and in erythropoietic protoporphyria. 13 Both diseases are usually thought to be transmitted as autosomal dominant traits with incomplete penetrance (protoporphyria) or variable expressivity (dominant spherocytosis) although, recessive forms with biallelic mutations have been documented in both diseases.…”

Section: Discussionmentioning

confidence: 87%

A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene

Grandchamp

Hetet

Kannengiesser

et al. 2011

Blood

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STEAP3/TSAP6 encodes a ferrireductase that is involved in the acquisition of iron by developing erythroblasts and steap3/ tsap6 null-mice display severe microcytic anemia. We report a family in which 3 siblings born to healthy parents display transfusion-dependent hypochromic anemia. A nonsense STEAP3/TSAP6 was identified in the siblings at the heterozygous state. This mutation was inherited from their father while no mutation was found in their mother. A large variability of expression was found between normal alleles in a control population, confirming a previous report that STEAP3/TSAPS6 is an expressed quantitative trait locus (e-QTL). Determination of the relative allele expression showed that the "normal" allele was expressed at a significantly higher level in the father than in the affected siblings relative to the shared mutated allele. The blood level of STEAP3/ TSAP6 mRNA was severely reduced in the siblings, while both parents were in the lower range of normal controls. The STEAP3/TSAP6 protein was also reduced in lymphocytic cell lines from the patients. Collectively, our data support the hypothesis that STEAP3/TSAP6 deficiency leads to severe anemia in the affected siblings and results from the combination of a mutated allele inherited from their father and a weakly expressed allele inherited from their mother. (Blood. 2011;118(25):6660-6666)

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Section: Discussionmentioning

confidence: 87%

A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene

Grandchamp

Hetet

Kannengiesser

et al. 2011

Blood

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“…9 The clinical severity of HE/HPP is influenced by the precise location and type of the structural αSp mutation, 6 as well as by the inheritance of modifying alleles, such as the hypomorphic SPTA αLELY polymorphism. 10 The SPTA αLELY haplotype has two point mutations that are invariably linked: a C>G mutation in codon 1857 of exon 40 and a C>T mutation in intron 45 of the SPTA gene that is responsible for partial skipping of exon 46 in 50% of the αSp mRNA. The six amino acids encoded by exon 46 are essential for the functional assembly of α/β SpD resulting in a reduced amount of αSp peptide from this locus.…”

Section: Introductionmentioning

confidence: 99%

Novel exon 2 spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct spectrin defects

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3Furthermore, the HPP phenotype is normocytic and not microcytic, and there are also numerous elliptocytes present on the peripheral smear; hence, we designate it as atypical HPP. In this manuscript, we clarify the molecular basis of these three phenotypes associated with the novel SPTA R34P mutation and provide new insight into the complexity of erythrocyte membrane disorders. Methods Clinical and routine laboratory studiesAll patients provided written, informed consent before participation in the study. The studies were approved by the University of Utah Institutional Review Board (IRB_00027669). Family AA 79-year old man (propositus of family A, A-I-3) ( Figure 1A) presented with a life-long history of anemia and intermittent jaundice. He and his extended family trace their ancestry to Scottish and Scandinavian forebears who were among the first Mormon settlers of Utah Territory. He had a splenectomy two years prior to presentation that resulted in a partial amelioration of his anemia. He was aware that multiple family members had a history of abnormal red blood cell morphology and some were anemic. His erythrocyte morphology revealed anisopoikilocytosis, fragmented cells, microspherocytes, elliptocytosis and polychromasia ( Figure 2A). Eleven first-degree relatives of his extended family over three generations were evaluated ( Figure 1A). Family BAn apparently unrelated 39-year old female (propositus of family B, B-I-1) ( Figure 3A) was referred to one of the Authors (JTP) for evaluation of very high platelet count and suspected essential thrombocythemia. Since red cell fragmentation can be mistakenly reported as elevated platelet count by laboratory instruments, the accuracy of elevated platelet count has been verified by semiquantitative estimation of platelet count by microscopic evaluation of blood smear by one of the Authors experienced with RBC fragmentation in several HPP patients identified over the last three decades (JTP). She had neonatal hyperbilirubinemia, and since birth has had episodes of jaundice with severe anemia (hemoglobin 70g/L). She had undergone splenectomy three years earlier, with improved anemia and no further episodes of jaundice. HerNovel α spectrin mutation and intragenic crossover haematologica | 2013; 98(12) 1973 ancestors were also among the first Mormon settlers of Utah Territory and were of north European ancestry. After splenectomy, she has had persistently elevated platelet counts (up to 1 million/mL), and was assumed to have essential thrombocythemia and treated intermittently with hydroxyurea. Her physical examination was unremarkable. Peripheral smear revealed significant anisopoikilocytosis, microspherocytes, elliptocytosis, and polychromasia ( Figure 2B). Further studies revealed polyclonal hematopoiesis determined by the X-chromosome transcriptional assay 12 and the absence of JAK2 and cMPL somatic mutations. The clinical diagnosis of atypical HPP and secondary thrombocytosis due to hemolytic anemia ...

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“…The polymorphism actually involves three linked mutations, which include: a point mutation at codon 1857 that changes a Leu to a Val, a point mutation in intron 45, and a point mutation in intron 46. Presumably as a result of one or both intron mutations, there is a 50% skipping of incorporation of exon 46 (residues 2177-2182) in the expressed protein (10). We previously showed the Leu 3 Val substitution did not affect incorporation of ␣ subunits into dimers and hence into red cell membranes, but the deletion of the 6 amino acids encoded by exon 46 prevented these subunits from being incorporated into the membrane, by reducing dimer binding affinity (33).…”

Section: Characterization Of Inter-and Intramolecular Cross-linked Pementioning

confidence: 99%

“…For example, most hereditary elliptocytosis and hereditary pyropoikilocytosis patients have mutations in one of the spectrin genes, and many of these mutations disrupt spectrin self-assembly into actin cross-linking tetramers (7)(8)(9). Spectrin mutations are usually heterozygous, and clinical severity of these mutations is frequently modulated by a common polymorphism, ␣ LELY , which affects the proportion of ␣ chains from each allele that are incorporated into the red cell membrane by affecting heterodimer assembly (10). Hence, both heterodimer and tetramer assembly are critical steps in producing a functional membrane skeleton and disruption of one or both of these processes is frequently the cause of hereditary anemias.…”

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confidence: 99%

A Structural Model of the Erythrocyte Spectrin Heterodimer Initiation Site Determined Using Homology Modeling and Chemical Cross-linking

Tang

Speicher

2008

Journal of Biological Chemistry

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Spectrin assembles into an anti-parallel heterodimeric flexible rod-like molecule through a multistep process initiated by a high affinity interaction between discrete complementary homologous motifs or "repeats" near the actin binding domain. Attempts to determine crystallographic structures of this critical dimer initiation complex have so far been unsuccessful. Therefore, in this study we determined the subunit-subunit docking interface and a plausible medium resolution structure of the heterodimer initiation site using homology modeling coupled with structural refinement based on experimentally determined distance constraints. Intramolecular and intermolecular cross-links formed by the "zero length" cross-linking reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were identified after trypsin digestion of cross-linked heterodimer complex using liquid chromatography-tandem mass spectrometry analysis. High confidence assignment of cross-linked peptides was facilitated by determination of cross-linked peptide masses with an uncertainty of a few parts per million using a high sensitivity linear ion trap mass spectrometer equipped with a Fouriertransform ion cyclotron resonance detector. Six interchain cross-links distinguished between alternative docking models, and these distance constraints, as well as three intrachain crosslinks, were used to further refine an initial homology-based structure. The final model is consistent with all available physical data, including protease protection experiments, isothermal titration calorimetry analyses, and location of a common polymorphism that destabilizes dimerization. This model supports the hypothesis that initial docking of the correct ␣ and ␤ repeats from among many very similar repeats in both subunits is driven primarily by long range electrostatic interactions.Spectrin is an actin cross-linking protein that lines the intracellular side of the plasma membrane of most cell types where it is a major component of a submembraneous scaffold. This membrane skeleton plays important roles in maintaining membrane integrity and organization, particularly in red cells. Red cell spectrin is composed of a 281-kDa ␣ subunit and a 246-kDa ␤ subunit that associate side-to-side in an anti-parallel orientation, and two heterodimers associate head-to-head to form a tetramer, which cross-links actin oligomers. The spectrin-actin membrane skeleton is linked to the membrane through several indirect linkages to transmembrane proteins as well as direct interactions with lipid head groups (1-6).Most hereditary hemolytic anemias, which are quite common in the human population, destabilize the red cell membrane by disrupting either the spectrin-actin scaffold or its linkages to the plasma membrane. For example, most hereditary elliptocytosis and hereditary pyropoikilocytosis patients have mutations in one of the spectrin genes, and many of these mutations disrupt spectrin self-assembly into actin cross-linking tetramers (7-9). Spectrin mutations are usually heterozygous, and clinical s...

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Low expression allele alpha LELY of red cell spectrin is associated with mutations in exon 40 (alpha V/41 polymorphism) and intron 45 and with partial skipping of exon 46.

Abstract: The av/41 polymorphism of erythroid a-spectrin has been characterized initially by an increased susceptibility to proteolysis of the aIV-aV domain junction (Alloisio N

Cited by 101 publications

References 29 publications

A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene

A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene

Novel exon 2 spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct spectrin defects

A Structural Model of the Erythrocyte Spectrin Heterodimer Initiation Site Determined Using Homology Modeling and Chemical Cross-linking

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