Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Towards improved diagnosis and treatment of rare inherited microcytic hypochromic anemias related to iron metabolism

Project Coordinator

INSERM U773 University Paris Diderot, Site Bichat


Clara Camaschella IRCCS San Raffaele Genetics and Biology Milano, Italy
Maria del Carmen Sanchez Institut de Medicina Predictiva I Personalitzada des Cancer (IMPPC) Genetics and Epigenetics of Cancer Barcelona, Spain
Martina Muckenthier Universitätsklinikum Heidelberd Department of Pediatric Hematology, Oncology and Immunology Heidelberg, Germany

Publications of the HMA-IRON project

Major results of the project

The daily production of red blood cells by the bone marrow is the most iron-requiring process in the body. Iron is provided by the destruction of senescent red blood cells by macrophages and the recycling of iron derived from hemoglobin catabolism. Intestinal iron absorption only compensates for the minor daily iron losses. The hormone hepcidin plays a major role in negatively controlling body iron availability. It is produced by the liver and adapts intestinal iron absorption and iron release from macrophages to the iron requirement of the bone marrow. Regulation of hepcidin production is extremely complex, involving multiple activators and repressors. A molecular defect in a repressor induces iron-restricted erythropoiesis whereas a defect in an activating pathway induces tissue iron overload. Iron restricted erythropoiesis results in the production of small red cells (microcytosis), containing an insufficient amount of hemoglobin (hypochromia). This leads to reduced oxygen supply to the body and impairs quality of life in the patients because of fatigue, dizziness and impaired cognitive functions.
The most frequent cause of microcytic anemia is nutritional iron deficiency, although gastro-intestinal bleedings can also cause important blood loss and iron deficiency. Increased hepcidin production that occurs during inflammatory syndromes also contributes to the onset of anemia. However, a number of hereditary causes of microcytic, hypochromic anemia have recently been described. This is a very heterogeneous group of disorders, involving molecular defects in genes that encode proteins necessary for iron acquisition by developing red cells or genes that encode hepcidin regulator(s). These hereditary anemias are rare, with the exception of the recently described Iron Deficiency Iron Refractory Anemia (IRIDA), which has probably been mostly underdiagnosed so far. The patients present with iron deficiency, abnormally high serum hepcidin levels and microcytic anemia. This disorder is due to mutations in a membrane-bound serine protease called Matriptase 2 (MT2) that normally downregulates hepcidin in conditions of low iron stores. This anemia is resistant to oral iron therapy, but can be usually corrected by intravenous iron therapy, underscoring  the importance of a proper diagnosis.
The aim of our project was to assemble a consortium of experts in the genetics of these rare anemias and in the control of iron homeostasis to better define the clinical and biological phenotypes of these disorders, to indentify new genes underlying these anemias and to perform functional studies of the mutated proteins.

We were able to recruit new patients with these rare anemias in France, Germany, Italy and Spain and to collect sufficient information to write a review on IRIDA that was published in Haematologica.
We identified 21 new IRIDA patients of several ethnic origins, we found 17 new MT2 mutations and performed functional analysis of eight mutations that affected protein function. These studies showed that the mutated proteins had lost their ability to auto-activate and to down-regulate hepcidin in conditions of low iron availability (This work has been accepetd for publication in Human Mutation).
We also identified a subtype of patients with microcytic anemia and iron deficiency that did not have MT2 mutations and presented low hepcidin levels; This new clinical entity was called IRIDA-like and high throughput sequencing strategy was applied to try to identify the gene defect underlying this anemia. Results are currently being analyzed. Finally, we described a new disorder due to mutation in the heme oxygenase gene.
Another approach was also taken to try to identify more hepcidin regulators that could be putative disease causative genes, using an ambitious genomewide siRNA screening method. Several new pathways were identified that highlighted links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis as well as nutrient metabolism. Functional studies of these new pathways are underway.
Altogether, this consortium contributed to a better knowledge of IRIDA, as well as to medical training of young investigators and to the opening of new centres providing genetic diagnosis and medical care for patients with microcytic anemias and other benign rare blood disorders (enzyme deficiencies, red cell membrane disorders…).

E-Rare 2012 - Created by Toussaint Biger