New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation
Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the <i>SLC11A2</i> 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. Muta...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/8/4406 |
| Summary: | Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the <i>SLC11A2</i> 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 <i>SLC11A2</i> 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 <i>SLC11A2</i> splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a <i>SLC11A2</i> 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. |
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| ISSN: | 1661-6596 1422-0067 |