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Article

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

by
Lídia Romero-Cortadellas
1,†,
Gonzalo Hernández
1,2,†,
Xènia Ferrer-Cortès
1,2,
Laura Zalba-Jadraque
2,
José Luis Fuster
3,
Mar Bermúdez-Cortés
3,
Ana María Galera-Miñarro
3,
Santiago Pérez-Montero
2,
Cristian Tornador
2 and
Mayka Sánchez
1,2,*
1
Iron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195 Sant Cugat del Vallès, Spain
2
BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain
3
Pediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(8), 4406; https://doi.org/10.3390/ijms23084406
Submission received: 16 March 2022 / Revised: 8 April 2022 / Accepted: 12 April 2022 / Published: 15 April 2022
(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)
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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.
Keywords: DMT1; microcytic anemia; iron overload; SLC11A2; mutation; EPO DMT1; microcytic anemia; iron overload; SLC11A2; mutation; EPO

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MDPI and ACS Style

Romero-Cortadellas, L.; Hernández, G.; Ferrer-Cortès, X.; Zalba-Jadraque, L.; Fuster, J.L.; Bermúdez-Cortés, M.; Galera-Miñarro, A.M.; Pérez-Montero, S.; Tornador, C.; Sánchez, M. New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation. Int. J. Mol. Sci. 2022, 23, 4406. https://doi.org/10.3390/ijms23084406

AMA Style

Romero-Cortadellas L, Hernández G, Ferrer-Cortès X, Zalba-Jadraque L, Fuster JL, Bermúdez-Cortés M, Galera-Miñarro AM, Pérez-Montero S, Tornador C, Sánchez M. New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation. International Journal of Molecular Sciences. 2022; 23(8):4406. https://doi.org/10.3390/ijms23084406

Chicago/Turabian Style

Romero-Cortadellas, Lídia, Gonzalo Hernández, Xènia Ferrer-Cortès, Laura Zalba-Jadraque, José Luis Fuster, Mar Bermúdez-Cortés, Ana María Galera-Miñarro, Santiago Pérez-Montero, Cristian Tornador, and Mayka Sánchez. 2022. "New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation" International Journal of Molecular Sciences 23, no. 8: 4406. https://doi.org/10.3390/ijms23084406

APA Style

Romero-Cortadellas, L., Hernández, G., Ferrer-Cortès, X., Zalba-Jadraque, L., Fuster, J. L., Bermúdez-Cortés, M., Galera-Miñarro, A. M., Pérez-Montero, S., Tornador, C., & Sánchez, M. (2022). New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation. International Journal of Molecular Sciences, 23(8), 4406. https://doi.org/10.3390/ijms23084406

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