New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation

Abstract

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron.

Iron from the gut: the role of divalent metal transporter 1

“…In humans, 10 published cases of SLC11A2 mutation have been reported, presenting onset hypochromic microcytic anemia at fetal stage (1 case), birth (6 cases), infancy (1 case), 3 months (1 case), and 13 years of age (1 case), indicating that congenital SLC11A2 mutation is extremely rare and has an early onset. ( 63 ) A single patient, diagnosed with hypochromic microcytic anemia during metrorrhagia treatment, carried compound heterozygosity of G212V and N491S in SLC11A2 and homozygosity of H63D in HFE , while no mutation was detected in SLC40A1 (ferroportin), HJV (homojuvelin), HAMP (hepatic antimicrobial peptide; also known as hepcidin), or TfR2 (transferrin receptor 2). ( 64 ) The hyperferritinemia detection in this patient suggested an overlap of hereditary hemochromatosis (HH), which is a disorder of the iron store regulators and is caused by HFE , SLC40A1 , HAMP , HJV , or TfR2 mutations.…”

Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects

“…Mutations of DMT1 are very rare and are generally associated to hypochromic microcytic anemia with iron overload. Only 10 patients have been described so far, and distinct missense and splicing mutations have been identified either in the homozygous or compound heterozygous state [ 74 , 75 ]. Not all missense variants have been fully characterized from a biochemical point of view, but mutations appear to affect DMT1 iron transport activity and/or subcellular localization.…”

“…On the other hand, mutation Asn419Ser caused improper protein trafficking. Gly75Arg is the only other homozygous variant identified so far; the replacement of glycine with arginine was shown to affect protein stability and lead to accumulation of DMT1 in lysosomes [ 75 ].…”

Iron Metabolism in the Disorders of Heme Biosynthesis

“…Ten patients suffering from hypochromic microcytic anemia, sometimes already present at birth, have been described as harboring mutations in SLC11A2. All individuals but two presented with liver iron overload (in the two more recent cases, liver iron levels have not been assessed yet) [196]. SLC11A2 encodes for divalent metal transporter 1 (DMT1), a ferrous iron importer in erythroblasts, duodenal cells, and macrophages.…”