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...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4406 |
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| author | Lídia Romero-Cortadellas Gonzalo Hernández Xènia Ferrer-Cortès Laura Zalba-Jadraque José Luis Fuster Mar Bermúdez-Cortés Ana María Galera-Miñarro Santiago Pérez-Montero Cristian Tornador Mayka Sánchez |
| author_facet | Lídia Romero-Cortadellas Gonzalo Hernández Xènia Ferrer-Cortès Laura Zalba-Jadraque José Luis Fuster Mar Bermúdez-Cortés Ana María Galera-Miñarro Santiago Pérez-Montero Cristian Tornador Mayka Sánchez |
| author_sort | Lídia Romero-Cortadellas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T10:34:04Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:34:04Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6607076eda8e4a17a7e4de5ac1184d122023-12-01T21:04:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238440610.3390/ijms23084406New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R MutationLídia Romero-Cortadellas0Gonzalo Hernández1Xènia Ferrer-Cortès2Laura Zalba-Jadraque3José Luis Fuster4Mar Bermúdez-Cortés5Ana María Galera-Miñarro6Santiago Pérez-Montero7Cristian Tornador8Mayka Sánchez9Iron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195 Sant Cugat del Vallès, SpainIron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195 Sant Cugat del Vallès, SpainIron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195 Sant Cugat del Vallès, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainPediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, SpainPediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, SpainPediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainIron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195 Sant Cugat del Vallès, SpainDivalent 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.https://www.mdpi.com/1422-0067/23/8/4406DMT1microcytic anemiairon overload<i>SLC11A2</i>mutationEPO |
| spellingShingle | Lídia Romero-Cortadellas Gonzalo Hernández Xènia Ferrer-Cortès Laura Zalba-Jadraque José Luis Fuster Mar Bermúdez-Cortés Ana María Galera-Miñarro Santiago Pérez-Montero Cristian Tornador Mayka Sánchez New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation International Journal of Molecular Sciences DMT1 microcytic anemia iron overload <i>SLC11A2</i> mutation EPO |
| title | New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation |
| title_full | New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation |
| title_fullStr | New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation |
| title_full_unstemmed | New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation |
| title_short | New Cases of Hypochromic Microcytic Anemia Due to Mutations in the <i>SLC11A2</i> Gene and Functional Characterization of the G75R Mutation |
| title_sort | new cases of hypochromic microcytic anemia due to mutations in the i slc11a2 i gene and functional characterization of the g75r mutation |
| topic | DMT1 microcytic anemia iron overload <i>SLC11A2</i> mutation EPO |
| url | https://www.mdpi.com/1422-0067/23/8/4406 |
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