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Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia
Andrew Crispin, … , Mark D. Fleming, Sarah Ducamp
Andrew Crispin, … , Mark D. Fleming, Sarah Ducamp
Published July 7, 2020
Citation Information: J Clin Invest. 2020;130(10):5245-5256. https://doi.org/10.1172/JCI135479.
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Research Article Genetics Hematology Article has an altmetric score of 4

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia

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Abstract

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.

Authors

Andrew Crispin, Chaoshe Guo, Caiyong Chen, Dean R. Campagna, Paul J. Schmidt, Daniel Lichtenstein, Chang Cao, Anoop K. Sendamarai, Gordon J. Hildick-Smith, Nicholas C. Huston, Jeanne Boudreaux, Sylvia S. Bottomley, Matthew M. Heeney, Barry H. Paw, Mark D. Fleming, Sarah Ducamp

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Figure 3

HSCB deficiency affects iron metabolism and hemoglobinization in K562 cells.

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HSCB deficiency affects iron metabolism and hemoglobinization in K562 ce...
(A) Western blots of 3 independent experiments of iron metabolism proteins in uninduced K562 cells infected with viruses encoding scrambled (shSC) and HSCB-specific shRNAs (sh1 and sh2) for 10 days. (B) Quantification of Western blots in A. shSC, sh1, and sh2 are indicated by black, red, and blue, respectively. (C and D) Western blots (C) and quantification (D) of iron metabolism proteins in uninduced K562 cells treated with shRNAs as in A and either iron (Fe) or the iron chelator desferrioxamine (DF), demonstrating reduced expression but retained response of iron-regulated proteins to iron concentrations. One representative blot of 3 independent experiments is shown. Two ferritin heavy chain (FTH) outliers were removed based on Grubbs’s test P < 0.05. (E and F) Transferrin receptor 1 (TFR1) cell surface expression by flow cytometry of cells in A and C, respectively. (G–J) K562 cells treated with shRNAs as in A and differentiated by exposure to sodium butyrate for 96 hours. Western blotting demonstrates alterations in iron metabolism proteins (G and H) and impaired hemoglobin F expression (I and J). Three independent experiments are shown. For all panels, mean expression ± SD is normalized to noninfected (NI) cells. ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, #P = 0.06, ##P = 0.07 vs. shSC.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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