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we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer.
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report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications
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A novel ALAS2 missense mutation in exon 9 affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate in X-linked sideroblastic anemia.
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a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented
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int-1-GATA site should be examined in patients with XLSA in clinical settings when no known mutation is found in ALAS2 exons.
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From pH jump experiments, comparable rates for the denaturation of the tertiary structure and PLP-microenvironment were discerned, indicating that the catalytic active site geometry strongly depends on the stable tertiary structural organization. Lastly, we demonstrate that partially folded ALAS tends to self-associate into higher oligomeric species at moderate GuHCl concentrations.
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data indicate that the X-linked protoporphyria variants possess enhanced ALAS activity and ALA dissociation rates, as well as distinct structural properties from those of wild-type hALAS
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In this article we add a novel mutation to the previously described 61 different ALAS2 mutations identified in X-linked sideroblastic anaemia patients.
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the primary deficiency in ferrochelatase leads to a secondary increase in ALAS2 expression.
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The ALAS2 Y365C mutation impairs pyridoxal 5'-phosphate binding to ALAS2, destabilizing the enzyme. X inactivation was not highly skewed in WBC from affected women. This X-linked dominant mutation perturbs erythropoiesis via cell-nonautonomous effects.
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the 130-base pair enhancer region located in the first intron of the ALAS2 gene should be examined in patients with congenital sideroblastic anemia in whom the gene responsible is unknown.
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5 families with X-linked sideroblastic anemia had mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene.
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Loss-of-function FECH and gain-of-function erythroid-specific ALAS2 mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria.
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ALAS2 gain-of-function mutations increas the specific activity (DeltaAT, DeltaAGTG and p.Q548X) or stability (DeltaG) of the enzyme, thereby leading to the increased erythroid protoporphyrin accumulation causing X-linked protoporphyria.
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A large gain-of-function domain within the C-terminus of ALAS2 is associated with X-linked dominant protoporphyria.
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Late-onset photosensitivity was caused by ALAS2 mutation in a family with dominant protoporphyria.
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X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the beta-subunit of succinyl-CoA synthetase (SUCLA2).
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the C-terminal region of ALAS2 protein may function as an intrinsic modifier that suppresses catalytic activity and increases the degradation of its protein, each function of which is enhanced by the Met567Ile mutation and Val562Ala mutation, respectively
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Data suggest that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.
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identification of five probands with sideroblastic anemia and ALAS2 R452S (due to SNP); all were African-American males; all presented with moderate anemia; the four adults presented with iron overload [a multi-case report from the United States]
