However, many cases of CSA remain genetically unexplained. Genes in multiple pathways contribute to the pathogenesis of CSA, including those involved in heme biosynthesis ( ALAS2, SLC25A38), mitochondrial Fe-S cluster assembly and transport ( ABCB7, GLRX5, HSPA9), mitochondrial protein synthesis (mtDNA deletions, TRNT1, LARS2, YARS2, PUS1), and mitochondrial energy metabolism (mtDNA deletions, MT-ATP6, SLC19A2, NDUFB11) ( 1). As the normal location of erythroid mitochondria is in the vicinity of the nucleus, the pathological iron deposits appear to ring the nucleus, resulting in the characteristic “ring sideroblast.” The mitochondrion is the nexus of iron metabolism in the erythroid progenitor, being the site of iron incorporation into protoporphyrin IX to form heme, and being essential for iron-sulfur (Fe-S) cluster biogenesis. The congenital sideroblastic anemias (CSAs) are a group of uncommon inherited blood disorders characterized by abnormal iron accumulation in the mitochondria of erythroid cells. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene. 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. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. 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. Therefore, we hypothesized that mutations in HSCB could also cause CSA. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. 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).
The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis.
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