Sideroblastic anemia, iron overload, and ALAS2 R452S in African-American males: phenotype and genotype features of five unrelated patients
AMERICAN JOURNAL OF HEMATOLOGY
Authors: Lee, Pauline L.; Reid, Thomas J., III; Bottomley, Sylvia S.; Barton, James C.
Abstract
There are few reports of X-linked sideroblastic anemia (XLSA), iron overload, and mutations in ALAS2 that encodes 5-aminolevulinate synthase 2 in persons of sub-Saharan African Native descent [1-3]. A 50-year-old African-American man presented with microcytic anemia and mild thrombocytopenia. He had sideroblastic anemia, severe iron overload, cirrhosis, mild cardiomyopathy, diabetes mellitus, and antiplatelet antibodies. He was hemizygous for ALAS2 R452S (exon 9; c. 1406C -> A) and heterozygous for HFE H63D, but had no coding region mutations in TFR2, HAMP, HJV, or SLC40A1. Specific activity of the R452S protein was 80% of that of the normal recombinant enzyme. Its kinetic characteristics did not differ from those of the wild-type protein. We identified four other probands with sideroblastic anemia and ALAS2 R452S; all were African-American males. The five individuals appear phenotypically homogeneous, presenting with moderate anemia; the four adults presented with iron overload. This report updates the occurrence of XLSA among race/ethnicity groups, and raises the possibility that ALAS2 R452S occurs only in persons of sub-Saharan African Native descent.
Iron loading inhibits ferroportin1 expression in PC12 cells
NEUROCHEMISTRY INTERNATIONAL
Authors: Chen, YM; Qian, ZM; Du, JR; Duan, XL; Chang, YZ; Wang, Q; Wang, CY; Ma, YM; Xu, YJ; Li, LZ; Ke, Y
Abstract
Ferroportin 1 (FP1 or MTP1/IREG1), the product of the SLC40A1 gene, is a main iron export protein in mammals. Its mRNA contains an iron response element (IRE) in its 5' untranslated region, but the way this gene is regulated by iron is still unclear. The existence of FP I in the brain has been recently confirmed. To better understand the role of this important transmembrane iron exporter in brain iron homeostasis, we investigated the effects of iron and nitric oxide (NO) on FP1 expression and that of a FP1 antibody on iron release in nerve growth factor-treated rat PC12 cells. We found that FP I expression was down-regulated by iron loading but stimulated by iron chelation and treatment with a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). In addition, a significant decrease in iron release was found in cells treated with a FP1 antibody. Our findings imply that regulation of FP1 by iron in the cells is at the transcriptional level, rather than by an IRE/IRP-mediated pathway. Based on our results and published data, it is suggested that the transcriptional and translational (IRP/IRE pathway) mechanisms of FP1 expression might both operate in a tissue-specific manner and that FP1 might have a role in iron export from PC12 cells. (c) 2005 Elsevier Ltd. All rights reserved.