Hematologic Diseases; Hemochromatosis; Anemia, Iron-Deficiency; Genetic Diseases, Inborn
Public Health Interests
Obesity Research Working Group
Iron is an essential metal required for many cellular processes, including hemoglobin synthesis in red blood cells; excess iron, however, causes oxidative damage that can lead to organ failure. Our laboratory is interested in elucidating the molecular mechanisms that regulate systemic iron balance through genetic study of patients with iron disorders and through phenotypic characterization of genetically engineered mouse models.
Extensive Research Description
Disorders of iron balance are major causes of morbidity and mortality that collectively affect a significant proportion of the global population. Iron deficiency, which impairs hemoglobin production, immune function, and cognitive development, affects the majority of preschool children and pregnant women in non-industrialized countries. Decreased availability of iron for developing red blood cells also contributes to anemia in patients with chronic kidney disease and inflammatory states. In contrast, in patients who require chronic red cell transfusions as well as those with genetic disorders such as hereditary hemochromatosis and congenital iron loading anemias, free iron causes oxidative damage to the heart, liver, and endocrine organs, which may lead to organ failure.
During my postdoctoral research with Dr. Nancy Andrews, we focused on patients with a puzzling form of iron deficiency anemia. Typically, iron deficiency anemia is an acquired condition due to nutritional deficiency or chronic blood loss and can be treated with oral forms of iron. However, the unusual patients we studied exhibited iron deficiency anemia that appeared congenital and compatible with recessive transmission, and their anemia failed to respond to oral iron therapy. Additionally, when these patients were treated with iron intravenously, bypassing mechanisms of intestinal iron uptake, their hematological responses remained sluggish and incomplete. We hypothesized that this phenotype, which we termed “Iron Refractory Iron Deficiency Anemia” (IRIDA), resulted from a novel genetic defect that impaired both iron absorption and iron utilization.
After mapping the IRIDA phenotype to a critical interval on chromosome 22q12-13, we used a positional candidate approach to show that IRIDA is caused by mutations in the gene TMPRSS6. TMPRSS6 encodes a transmembrane serine protease expressed by the liver; the group of Dr. Ernest Beutler had recently reported that mice homozygous for a Tmprss6 splicing mutation displayed systemic iron deficiency and high hepatic levels of mRNA encoding the hepcidin hormone. Working in collaboration with the group of Dr. Mark Fleming, we accordingly found a spectrum of loss of function mutations in TMPRSS6 in the IRIDA kindreds. While the body’s normal response to iron deficiency is to reduce hepcidin synthesis in order to promote iron uptake from the diet, we found that hepcidin levels in IRIDA patients were paradoxically elevated. The hepcidin elevation in IRIDA patients explained their failure to absorb oral iron despite systemic iron deficiency as well as their incomplete response to intravenous iron formulations, which require processing by macrophages prior to utilization in erythropoiesis. Our genetic analysis of the IRIDA kindreds established that TMPRSS6 is essential for hepcidin regulation and thus maintenance of systemic iron homeostasis in humans.
The mechanism by which loss of TMPRSS6 activity led to hepcidin elevation, however, remained unclear. Signaling by bone morphogenetic proteins (BMPs) had recently emerged as a key pathway promoting hepcidin transcription in hepatocytes. The membrane-associated protein hemojuvelin (HJV), which acts as a co-receptor for BMPs, had been shown to be essential for hepcidin induction through the BMP pathway. We hypothesized that the elevated hepcidin expression in IRIDA resulted from excessive signaling through the BMP pathway. In support of this, we found that mRNA levels of several BMP target genes were elevated in livers of Tmprss6 knockout (Tmprss6-/-) mice. Using genetic mouse models, we showed that the hepcidin elevation and systemic iron deficiency observed in the setting of Tmprss6 mutation were dependent upon the presence of hemojuvelin. Together, our findings in mouse models suggested that down-regulation of hepatic BMP signaling by TMPRSS6 is required for maintenance of systemic iron balance. Our findings in mice were compatible with key in vitro work from the group of Dr. Clara Camaschella that showed TMPRSS6 can cleave hemojuvelin from the plasma membrane.
Hepcidin insufficiency is a feature of several genetic forms of iron overload. In these disorders, a failure of hepcidin to appropriately limit the absorption of dietary iron leads to tissue damage in organs such as the liver, heart, and endocrine glands. Because TMPRSS6 down-regulates hepcidin transcription, we hypothesized that disruption of TMPRSS6 activity would raise hepcidin levels, and therefore limit iron uptake, in this group of disorders. In a mouse model of β-thalassemia, a congenital iron loading anemia in which the bone marrow is postulated to release a hepcidin-repressing factor into the circulation, we found that the pathological hepcidin suppression that leads to iron loading did not occur in the absence of Tmprss6; thus, this study suggested that Tmprss6 is required for the action or production of the putative hepcidin-suppressing factor. In a mouse model of HFE-hemochromatosis (HFE-HH), in which the local loss of HFE function in the liver impairs hepcidin synthesis, we found that heterozygous loss of Tmprss6 markedly reduced iron loading. This result suggested that pharmacological inhibition of TMPRSS6 might prove an effective therapy in human HFE-HH and that common polymorphisms in TMPRSS6 might contribute to the variable clinical penetrance observed in this disorder.
For many iron disorders, existing treatments are limited and suboptimal. Incomplete understanding of the set of gene products that regulate hepcidin expression and systemic iron homeostasis represents an important knowledge gap that will hinder the development of new therapies. The long-term goal of my laboratory is to elucidate molecular mechanisms underlying iron physiology through genetic study of patients with iron phenotypes and through characterization of genetically targeted mouse models.
Ironing out the role of Toll-like receptors
Finberg KE. Ironing out the role of Toll-like receptors. Blood. 2015;125:2183-4.
Iron-Refractory Iron Deficiency Anemia (IRIDA)
Heeney MM and Finberg KE. Iron-Refractory Iron Deficiency Anemia (IRIDA). Hematol Oncol Clin North Am. 2014;28:637-652.
Striking the target in iron overload disorders
Finberg KE. Striking the target in iron overload disorders. J Clin Invest 2013;123:1424-7.
Regulation of systemic iron homeostasis
Finberg KE. Regulation of systemic iron homeostasis. Curr Opin Hematol 2013;20:208-214.
Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
Finberg KE, Whittlesey RL, Andrews NC. Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood 2011;117:4590-4599.
Unraveling mechanisms regulating systemic iron homeostasis
Finberg KE. Unraveling mechanisms regulating systemic iron homeostasis. Hematology Am Soc Hematol Educ Program 2011;2011:532-537.
Downregulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis
Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Downregulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 2010;115:3817-3826.
Iron-refractory, iron deficiency anemia
Finberg KE. Iron-refractory, iron deficiency anemia. Semin Hematol 2009;46:378-386.
Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)
Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos, K, Andrews NC, Fleming MD. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008;40:569-571.
Full List of PubMed Publications
- Heeney MM, Finberg KE: Iron-refractory iron deficiency anemia (IRIDA). Hematol Oncol Clin North Am. 2014 Aug; 2014 May 28. PMID: 25064705
- Finberg KE: Regulation of systemic iron homeostasis. Curr Opin Hematol. 2013 May. PMID: 23426198
- Finberg KE: Striking the target in iron overload disorders. J Clin Invest. 2013 Apr; 2013 Mar 25. PMID: 23524962
- Khuong-Quang DA, Schwartzentruber J, Westerman M, Lepage P, Finberg KE, Majewski J, Jabado N: Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy. Pediatrics. 2013 Feb; 2013 Jan 14. PMID: 23319530
- Finberg KE, Whittlesey RL, Andrews NC: Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood. 2011 Apr 28; 2011 Feb 25. PMID: 21355094
- Finberg KE: Unraveling mechanisms regulating systemic iron homeostasis. Hematology Am Soc Hematol Educ Program. 2011. PMID: 22160085
- Finberg KE, Whittlesey RL, Fleming MD, Andrews NC: Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010 May 6; 2010 Mar 3. PMID: 20200349
- Finberg KE: Iron-refractory iron deficiency anemia. Semin Hematol. 2009 Oct. PMID: 19786206
- Finberg KE: Iron homeostasis: casting new roles. Blood. 2008 Sep 15. PMID: 18779402
- Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, Fleming MD: Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008 May; 2008 Apr 13. PMID: 18408718