Lesional Mechanism of Alpha Thalassemias : Towards a Common Mechanism Alpha Thal / Beta Thal
Serge PissardFlavia GuillemElisa Domingues‐HamdiMichaël DussiotThunwarat SuriyunOlivier HermineVeronique Baudin creuzaG. Courtois
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Alpha-thalassemia
Alpha (finance)
Ineffective erythropoiesis
Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the α- or the β-chain of hemoglobin. The expressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of α-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the α-thalassemia mutation resides [129 sv/ev /129 sv/ev (severe) or 129 sv/ev /C57BL/6 (mild)]. Linkage mapping indicates that the modifying gene is very tightly linked to the β-globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype correlates with the size of β-chain-containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The β-major globin chains encoded by the two strains differ by three amino acids, one of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should be available for interchain disulfide bridging and consequent aggregation between excess β-chains. This normal polymorphic variation between murine β-globin chains could account for the modifying action of the unlinked β-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between α- and β-chains but on the chemical nature of the normal β-chain, which is in excess. This work also indicates that modifying genes can be normal variants that—absent an apparent physiologic rationale—may be difficult to identify on the basis of structure alone.
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BETA (programming language)
Alpha (finance)
Alpha chain
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Reticulocytosis
Heterotetramer
Cooperativity
Bohr effect
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Beta-thalassemias are heterogeneous autosomal recessive hereditary anemias characterized by reduced or absent β globin chain synthesis. The resulting relative excess of unbound α globin chains precipitate in erythroid precursors in the bone marrow, leading to their premature death and, hence, to
Beta thalassemia
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α1-antitrypsin (α1-AT) is a 52 kDa sialoglycoprotein. The function of α1-antitrypsin is to protect the lower respiratory tract of lungs from proteolytic degradation by neutrophil elastase. Severe genetic deficiency of α1-AT is associated with early onset emphysema and liver diseases. α1-AT also exhibits anti-inflammatory activities independent of its protease inhibitor function. There are over 90 genetic variants of human α1-antitrypsin. These variants occur due to amino acid substitution / deletion which results in charge differences. Based on charge differences these variants have been identified by isoelectric focusing. The two most common deficiency variants are S and Z. The S variant migrates anodal to Z variant. The Z variant migrates most cathodal in isoelectric focusing, hence named Z. In Z variant, the β-sheet A undergoes expansion , therefore it can easily accept the reactive site loop of a second α1-AT molecule and consequently form polymers of α1-AT. These polymers of α1-AT aggregate in the hepatocytes and show liver and lungs diseases. Contrary to this, the S variant of α1-AT is not associated with any significant clinical disease because the conformation of the inhibitor is not altered significantly. The Z related pathologies could be treated by liver transplantation, augmentation therapy, gene therapy, peptide therapy and chemical chaperone therapy. In addition to common deficiency variants, there are several rare deficiency variants of α1-AT like Siiyama , Mmalton , Mprocida, Mheerlen, Mmineral springs, Mnichinan, Pduarte, Wbethesda Zaugsberg, and Zbristol. In Siiyama , Mmalton , Mnichinan and Zaugsberg, the β-sheet A is present in an open state, therefore these variants readily undergo polymerization and consequently show aggregation in the hepatocytes. In Mprocida, Mheerlen, Mmineral springs, Pduarte and Wbethesda the conformation is altered significantly, therefore these variants become conformationally less stable and thereby undergo intracellular proteolysis. These rare genetic variants show lungs and / or liver disease. There are several null variants of α1-AT that are not detected either at the stage of transcription or translation. The examples of some of the null variants are QOcardiff, QOhong kong, QOgranite falls, QObellingham, QOmattawa, QObolton, and QOludwigshafen. The molecular basis of deficiency of these variants also form the theme of this review. Keywords: α1-antitrypsin, aggregation, emphysema, genetic variants of α1-antitrypsin, intracellular proteolysis, liver diseases, serpins superfamily
Alpha 1-antitrypsin deficiency
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The classical form of α1-antitrypsin (α1-AT) deficiency is associated with a mutant α1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of α1-AT in a family in which three affected members had severe liver disease associated with α1-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes α1-ATZ as well as the mutation that characterizes α1-AT Saarbrucken (α1-AT saar). The mutation in PIsaar introduces a premature termination codon resulting in an α1-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the α1-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of α1-AT saar and α1-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant α1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in α1-AT deficiency.
Heterozygote advantage
Liver disease
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Ineffective erythropoiesis
Alpha-thalassemia
Reticulocytosis
Microcytic anemia
Proband
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Recently, the small protein α hemoglobin–stabilizing protein (AHSP) was identified and found to specifically bind α-globin, stabilize its structure, and limit the toxic effects of excess α-globin, which are manifest in the inherited blood disorder β thalassemia. In this issue of the JCI, Yu, Weiss, and colleagues show that AHSP is also critical to the formation and stabilization of normal amounts of hemoglobin, even when α-globin is deficient, indicating unique and previously unidentified roles for this molecule (see the related article beginning on page 1856).
Alpha globulin
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BETA (programming language)
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Hb M-Iwate [alpha 87 (F8) His-->Tyr] was identified as the cause of cyanosis in a 21-year-old Japanese female. Amplification and sequencing of the alpha 2- and alpha 1-genes demonstrated the mutation CD87 CAC (His)-->TAC (Tyr) in the alpha 2-gene. Analysis of the in vitro globin biosynthesis in the reticulocytes disclosed a well-balanced beta/alpha synthetic ratio of 1.04 but an unexpectedly low alpha M/total alpha. Although the cause of the lowered alpha M-globin biosynthesis is not yet clear, it might be related to a defect in chain assembly rather than to a modified stability or a reduced amount of the abnormal alpha-globin mRNA.
Alpha (finance)
Alpha chain
genomic DNA
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