Iron metabolism: regulation and diseases

  • Mayka Sanchez Group
Campus ICO-Germans Trias i Pujol

Josep Carreras Leukaemia Research Institute
Edifici IMPPC
Can Ruti CampusCtra de Can Ruti
Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

Office 2-12, Lab 2-20 (second floor)



Iron Metabolism: Regulation and Diseases

Iron is an essential micronutrient for both benign and neoplastic cells and a tight regulation of its metabolism is crucial for health. Iron deficiency leads to anemia, a major world-wide public health problem, and iron overload increases the oxidative stress of body tissues leading to inflammation, cell death, system organ dysfunction, and cancer.

Inherited or acquired iron-related anaemias are a subset of heterogeneous diseases, some of them with a poor prognostic and quality of life for the patient and requiring bone marrow transplantation for a complete cure of the disease (i.e. Sideroblastic Anaemia non-responsive to pyridoxine, gen SLC25A38). Currently, in the unit Diagnostics in Iron Metabolism Diseases (D·IRON), we perform 21 genetic diagnostics for germ-line and acquired iron-related diseases, including the study of Myelodysplastic Syndrome (MDS) with ring sideroblasts (refractory anemia with sideroblasts ring, RARS, gene SF3B1).

The IRP/IRE post-transcriptional regulatory system is a key network controlling cellular iron homeostasis. The iron regulatory proteins (IRP1 and IRP2) can recognize a cis-regulatory mRNA motif termed IRE (iron responsive element), a conserved RNA element located in the untranslated regions (UTR) of mRNAs that encode proteins involved in iron metabolism. Our recent findings suggest that the IRP/IRE regulatory network is wider than previously thought, and include genes involved in cancer progression and metastasis.


The research in our laboratory is centred on the following research lines:

  • Molecular and genetic studies in patients referred to our center for genetic diagnosis on rare iron metabolism diseases and implementation of a novel diagnostic technology based on targeted next-generation sequencing (MiSeq).
  • Discovery of novel rare diseases in iron metabolism by exome sequencing.
  • Characterization of new mRNAs regulated by IRPs and potentially involved in cancer. These studies may represent an important step in the establishment of new neoplastic markers.
  • Implementation of telemedicine tools such as HIGHFERRITIN in order to help with the diagnosis and management of patients
  • Study the role of new mRNAs regulated by the IRP/IRE system in the pathogenesis of Myelodysplastic Syndrome (MDS) with ring sideroblasts in collaboration with the group of Dr. Norbert Gattermann (Düsseldorf).


  • Prof. Dr. Matthias W. Hentze, M.D. Associate Director of European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. 
  • Prof. Dr. Martina U. Muckenthaler, PhD. Head of Molecular Medicine. University of Heidelberg, Germany.
  • Dr. Vladimir Benes, PhD. Head of GeneCore Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Prof. Dr. Norbert Gattermann, Klinik für Hämatologie, Onkologie und klin. Immunologie, Geschäftsführender Leiter des Universitätstumorzentrums (UTZ), Heinrich-Heine-Universität Düsseldorf.
  • Whole Genix, WG is a bioinformatic company focused on interpreting genomic variations and producing clinical report in patients with neoplastic diseases, providing the oncologist relevant information to the application of personalized or precise medicine. 
  • Convenio APU-ADISCON, Asociación de familiares y enfermos de anemia diseritropoyética congénita (ADISCON) y a la Asociación Pablo Ugarte (APU)


Former members

Sara LuscietiPhD Student
Anna Barqué
PhD Student

Selected publications

Joshi R, Shvartsman M, Morán E, Lois S, Aranda J, Barqué A, de la Cruz X, Bruguera M, Vagace JM, Gervasini G, Sanz C, Sánchez M

Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.

Mol Genet Genomic Med May 2015, 3 (3) 221-32. Epub 6 Mar 2015
Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.
More information
De Falco L, Silvestri L, Kannengiesser C, Morán E, Oudin C, Rausa M, Bruno M, Aranda J, Argiles B, Yenicesu I, Falcon-Rodriguez M, Yilmaz-Keskin E, Kocak U, Beaumont C, Camaschella C, Iolascon A, Grandchamp B, Sanchez M

Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies.

Hum. Mutat. Nov 2014, 35 (11) 1321-9. Epub 10 Sep 2014
Iron-refractory iron-deficiency anemia (IRIDA) is a rare autosomal-recessive disorder characterized by hypochromic microcytic anemia, low transferrin saturation, and inappropriate high levels of the iron hormone hepcidin. The disease is caused by variants in the transmembrane protease serine 6 (TMPRSS6) gene that encodes the type II serine protease matriptase-2, a negative regulator of hepcidin transcription. Sequencing analysis of the TMPRSS6 gene in 21 new IRIDA patients from 16 families with different ethnic origin reveal 17 novel mutations, including the most frequent mutation in Southern Italy (p.W590R). Eight missense mutations were analyzed in vitro. All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation. Genotype-phenotype studies in IRIDA patients have been so far limited due to the relatively low number of described patients. Our genotype-phenotype correlation analysis demonstrates that patients carrying two nonsense mutations present a more severe anemia and microcytosis and higher hepcidin levels than the other patients. We confirm that TMPRSS6 mutations are spread along the gene and that mechanistically they fully or partially abrogate hepcidin inhibition. Genotyping IRIDA patients help in predicting IRIDA severity and may be useful for predicting response to iron treatment.
More information
Athiyarath R, Arora N, Fuster F, Schwarzenbacher R, Ahmed R, George B, Chandy M, Srivastava A, Rojas AM, Sanchez M, Edison ES

Two novel missense mutations in iron transport protein transferrin causing hypochromic microcytic anaemia and haemosiderosis: molecular characterization and structural implications.

Br. J. Haematol. Nov 2013, 163 (3) 404-7. Epub 24 Jul 2013More information
Luscieti S, Tolle G, Aranda J, Campos CB, Risse F, Morán É, Muckenthaler MU, Sánchez M

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome.

Orphanet J Rare Dis 2013, 8 30. Epub 19 Feb 2013
Hereditary Hyperferritinaemia Cataract Syndrome (HHCS) is a rare autosomal dominant disease characterized by increased serum ferritin levels and early onset of bilateral cataract. The disease is caused by mutations in the Iron-Responsive Element (IRE) located in the 5' untranslated region of L-Ferritin (FTL) mRNA, which post-transcriptionally regulates ferritin expression.
More information
Sanchez M, Galy B, Schwanhaeusser B, Blake J, Bähr-Ivacevic T, Benes V, Selbach M, Muckenthaler MU, Hentze MW

Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins.

Blood 24 Nov 2011, 118 (22) e168-79. Epub 22 Sep 2011
Iron regulatory proteins (IRPs) 1 and 2 are RNA-binding proteins that control cellular iron metabolism by binding to conserved RNA motifs called iron-responsive elements (IREs). The currently known IRP-binding mRNAs encode proteins involved in iron uptake, storage, and release as well as heme synthesis. To systematically define the IRE/IRP regulatory network on a transcriptome-wide scale, IRP1/IRE and IRP2/IRE messenger ribonucleoprotein complexes were immunoselected, and the mRNA composition was determined using microarrays. We identify 35 novel mRNAs that bind both IRP1 and IRP2, and we also report for the first time cellular mRNAs with exclusive specificity for IRP1 or IRP2. To further explore cellular iron metabolism at a system-wide level, we undertook proteomic analysis by pulsed stable isotope labeling by amino acids in cell culture in an iron-modulated mouse hepatic cell line and in bone marrow-derived macrophages from IRP1- and IRP2-deficient mice. This work investigates cellular iron metabolism in unprecedented depth and defines a wide network of mRNAs and proteins with iron-dependent regulation, IRP-dependent regulation, or both.
More information
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Current projects

Doctoral Student:Towards the improvement of diagnosis and treatment in Congenital Dyserythropoyetic anaemia type 2

Project leader:Mayka Sanchez
Start date:03/08/2015
End date:02/08/2018

Uncovering new molecular and pathophysiological networks in iron metabolism

Project leader:Mayka Sanchez
Start date:01/01/2016
End date:31/12/2018

Towards the improvement of diagnosis and treatment in Congenital Dyserythropoyetic Anaemias Título: Hacia la mejora del diagnóstico y tratamiento en anemias diseritropoyéticas congénitas

Project leader:Mayka Sanchez
Code:CoDysAn project
Start date:01/01/2017
End date:31/12/2020

Incentive Programme for the Incorporation and Intensification of Research Activity

Project leader:Mayka Sanchez
Start date:01/01/2017
End date:31/12/2020

Refining and improving a NGS gene panel for clinical diagnosis of hereditary hematologic diseases and discovery of new genes. Whole Genix SL, University of Vic

Project leader:Mayka Sanchez
Code:2016 DI013
Start date:01/01/2017
End date:31/12/2018

Previous projects

Role of new IRP-Target MRNAS in Cancer and Iron Biology

Project leader:Mayka Sanchez
    Start date:01/01/2013
    End date:31/12/2015

    Translational Research on rare diseases of iron metabolism by massively parallel sequencing

    Project leader:Mayka Sanchez
    Start date:27/06/2012
    End date:26/06/2015

    Deutsche Josep Carreras Leukämie-Stiftung

    Project leader:Mayka Sanchez
    Code:DJCLS R 14/04
    Start date:01/01/2014
    End date:31/12/2016

    Estudios moleculares de enfermedades genéticas raras del metabolismo del hierro: de la anemia congénita a la Hemocromatosis hereditaria no-HFE

    Project leader:Mayka Sanchez
    Start date:01/01/2010
    End date:31/12/2012

    Program I3 (PI3) Incentive Program for the Incorporation and Intesification of Research Activity

    Project leader:Mayka Sanchez
    Code:PI3_Mayka 2015
      Start date:01/01/2015
      End date:31/03/2017

      Contract for reintegration of outstanding researchers (Ramón y Cajal contract)

      Project leader:Mayka Sanchez
        Start date:01/01/2009
        End date:31/12/2014

        Competitive grant to help Junior Groups in hiring Technician Support for Research in Health

        Project leader:Mayka Sanchez
        Start date:01/01/2011
        End date:31/12/2013

        FEBS postdoctoral fellowship (2012-1015)

        Project leader:Mayka Sanchez
          Start date:01/01/2012
          End date:31/12/2014

          e-ENERCA (Coordinator Dr Joan-Lluis Vives-Corrons) Collaborating partner in WP2, WP5 and WP6: Dr Mayka Sanchez

          Project leader:Mayka Sanchez
          Start date:01/10/2013
          End date:31/10/2016

          Consolider-Ingenio, RNA-REG (Coordinator Dr Juan Valcarcel) Dr Mayka Sanchez was selected for the Young Investigator Programme

          Project leader:Mayka Sanchez
            Start date:01/02/2010
            End date:31/12/2015

            EMBO short fellowship

            Project leader:Sara Luscieti
            Code:ASTF 301-2013
            Start date:16/09/2013
            End date:15/12/2013