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Corrigendum Free access | 10.1172/JCI132538

X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

Vijay G. Sankaran, Jacob C. Ulirsch, Vassili Tchaikovskii, Leif S. Ludwig, Aoi Wakabayashi, Senkottuvelan Kadirvel, R. Coleman Lindsley, Rafael Bejar, Jiahai Shi, Scott B. Lovitch, David F. Bishop, and David P. Steensma

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Published January 2, 2020 - More info

Published in Volume 130, Issue 1 on January 2, 2020
J Clin Invest. 2020;130(1):552–552. https://doi.org/10.1172/JCI132538.
© 2020 American Society for Clinical Investigation
Published January 2, 2020 - Version history
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Related article:

X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation
Vijay G. Sankaran, … , David F. Bishop, David P. Steensma
Vijay G. Sankaran, … , David F. Bishop, David P. Steensma
Brief Report Hematology

X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

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Abstract

Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5′-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5′-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease.

Authors

Vijay G. Sankaran, Jacob C. Ulirsch, Vassili Tchaikovskii, Leif S. Ludwig, Aoi Wakabayashi, Senkottuvelan Kadirvel, R. Coleman Lindsley, Rafael Bejar, Jiahai Shi, Scott B. Lovitch, David F. Bishop, David P. Steensma

×

Original citation: J Clin Invest. 2015;125(4):1665–1669. https://doi.org/10.1172/JCI78619

Citation for this corrigendum: J Clin Invest. 2020;130(1):552. https://doi.org/10.1172/JCI132538

The amino acid substitution for the ALAS2 mutation was incorrectly noted in the original article. The correct designation is ALAS2 Y365H. The correct sentences and figure part are below.

Abstract:

We determined that this mutation (Y365H) impairs binding of the essential cofactor pyridoxal 5′-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function.

Results and Discussion:

This A-to-G variant was found at position 55042086 on the X chromosome (hg19 coordinates), resulting in a coding change of Y365H in the ALAS2 protein (Figure 1F and Supplemental Figure 1).

By modeling this novel ALAS2 Y365H mutation in the structure of the Rhodobacter capsulatus homolog, we noted that Y365 fits within a hydrophobic core critical for binding the essential cofactor pyridoxal 5′-phosphate (PLP) (Figure 2A and ref. 16).

Together, these findings indicate that the Y365H mutation markedly impairs PLP binding, which may account for some or all of the substantially reduced stability of the ALAS2 enzyme.

Figure 2 legend:

Severe LOF with the ALAS2 Y365H mutation and lack of highly skewed X inactivation in female mutation carriers. (A) Model of ALAS2 shows PLP highlighted in blue and the Y or H amino acid at position 365 highlighted in red.

The authors regret the errors.

Footnotes

See the related article at X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation.

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  • Version 1 (January 2, 2020): Print issue publication

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