Karin Finberg, MD, PhD
Research & Publications
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 research employs genetic approaches in human patients and mouse models to define the molecular basis of inherited iron disorders, mechanisms of systemic iron regulation, and physiological consequences of iron deficiency anemia. Our long-term goal is to identify molecular targets for therapeutic intervention in genetic and acquired defects in iron metabolism.
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.
Iron-Refractory Iron Deficiency Anemia (IRIDA): A congenital anemia caused by mutations in TMPRSS6
Iron deficiency anemia is typically an acquired disorder; however, atypical cases of iron deficiency anemia have been reported in which the clinical presentation and family history suggested an unknown genetic basis. My early postdoctoral work showed that mutations in the hepatic transmembrane serine protease TMPRSS6 cause Iron-Refractory, Iron Deficiency Anemia (IRIDA), a recessive disorder which is classically characterized by iron deficiency anemia unresponsive to oral iron therapy but partially responsive to intravenous iron. As IRIDA patients show inappropriate elevation of the iron regulatory hormone hepcidin, this work established that TMPRSS6 is essential for hepcidin regulation, and thus maintenance of systemic iron homeostasis, in humans. Because hepcidin inhibits duodenal iron absorption and macrophage iron release, the hepcidin elevation in IRIDA provides insight into the underlying pathophysiology, explaining the failure to absorb dietary iron despite systemic iron deficiency as well as the incomplete response to parenteral forms of iron, which must be processed and exported by macrophages prior to utilization in erythropoiesis. In subsequent collaborations, we showed that the spectrum of clinical iron phenotypes associated with germline TMPRSS6 mutations extends beyond the classic IRIDA phenotype, and we developed a clinical laboratory metric that predicts TMPRSS6 mutation status in patients with chronic iron deficiency. By defining clinical and genetic criteria for this disorder, our findings have enabled the development of diagnostic algorithms for patients with iron-refractory anemia.
TMPRSS6 down-regulates hepcidin production by dampening hepatic BMP signaling
The mechanism by which loss of TMPRSS6 activity led to hepcidin elevation, however, remained unclear. Signaling by bone morphogenetic proteins (BMPs) had been established as key pathway promoting hepcidin transcription in hepatocytes. We showed that genetic loss of Tmprss6 causes excessive hepatic BMP signaling. Additionally, we found that the hepcidin elevation and systemic iron deficiency observed in mice with Tmprss6 loss were dependent upon the presence of hemojuvelin, a membrane-associated BMP co-receptor. Together, our findings in mouse models suggested that down-regulation of hepatic BMP signaling by TMPRSS6 is required for maintenance of systemic iron balance. Additionally, in a mouse model of HFE-hemochromatosis (HFE-HH), a clinical iron overload disorder characterized by impaired hepcidin synthesis, we showed that disruption of Tmprss6 raises hepcidin and therefore limits iron uptake. Our findings in mouse models provided proof-of-concept for the clinical development of TMPRSS6-targeted therapies for the treatment of HFE-HH and other clinical iron-loading disorders characterized by hepcidin insufficiency.
Elucidation of effects of iron deficiency on hematopoiesis
My group has employed the Tmprss6 mouse model as a tool to define the effects of iron restriction on hematopoiesis, an area with key relevance for development of therapeutic approaches based on TMPRSS6 inhibition. Notably, in both humans and mice with TMPRSS6 mutations, anemia is accompanied by elevated platelet counts. In a collaboration with the group of Dr. Diane Krause (Yale), we showed that megakaryocytic (Mk)-erythroid progenitor cells (MEPs) from Tmprss6-/- mice are biased toward the Mk lineage. We observed a similar Mk bias in non-transgenic mice with acquired iron deficiency anemia, providing an explanation for the frequent clinical association of thrombocytosis and iron deficiency anemia. My group has also defined the erythropoietic consequences of genetic loss of Tmprss6 in a mouse model of non-transfusion dependent β-thalassemia, a congenital iron-loading anemia in which ineffective erythropoiesis-induced hepcidin suppression contributes to systemic iron loading. We found that Tmprss6 loss altered terminal erythroid differentiation but did not raise hemoglobin levels. These findings suggest that the application of TMPRSS6-targeted therapies will require careful titration to prevent deleterious consequences of systemic iron restriction.
Elucidation of pathophysiological consequences of iron deficiency beyond hematopoiesis
Recent work in humans and mouse models has suggested that iron deficiency is associated with elevations in circulating levels of fibroblast growth factor 23 (FGF23), a hormone classically thought to be produced by osteocytes in bone, which regulates systemic phosphate homeostasis by inhibiting renal phosphate reabsorption and by suppressing levels of the active form of vitamin D. In collaboration with Dr. Jackie Fretz (Yale), we have found that Tmprss6-/- mice show elevated circulating levels of the active FGF23 hormone and disrupted phosphate homeostasis, and we have identified sinusoidal endothelial cells of the bone marrow as a novel site of FGF23 production in iron deficiency anemia and after acute blood loss. We have also collaborated with Dr. Fretz to dissect the contribution of iron deficiency to FGF23 regulation in her mouse model of congenital chronic kidney disease.
Therapeutic phlebotomy is the standard of care to reduce liver iron accumulation in HFE-HH, although the underlying molecular mechanisms that mediate hepatic mobilization of hepatic iron stores have remained poorly understood. My laboratory showed that NCOA4, a cytosolic protein known to direct the iron storage protein ferritin to lysosomes, is required locally for the release of iron from storage sites in the liver after blood loss. Additionally, we reported that NCOA4 expression is upregulated by hypoxia inducible factors (HIFs). By implicating HIFs in NCOA4 regulation, these studies suggest novel, mechanistic links between hypoxia, iron deficiency, and ferritin degradation.
Blood; Blood Cells; Hematologic Diseases; Hematopoiesis; Hemochromatosis; Liver Diseases; Anemia, Iron-Deficiency; Genetic Diseases, Inborn
Public Health Interests
Genetics, Genomics, Epigenetics
- IL‐1β Drives Production of FGF‐23 at the Onset of Chronic Kidney Disease in MiceMcKnight Q, Jenkins S, Li X, Nelson T, Marlier A, Cantley LG, Finberg KE, Fretz JA. IL‐1β Drives Production of FGF‐23 at the Onset of Chronic Kidney Disease in Mice Journal Of Bone And Mineral Research 2020, 35: 1352-1362. PMID: 32154933, PMCID: PMC7363582, DOI: 10.1002/jbmr.4003.
- NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood lossLi X, Lozovatsky L, Sukumaran A, Gonzalez L, Jain A, Liu D, Ayala-Lopez N, Finberg KE. NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss Blood 2020, 136: 2691-2702. PMID: 32659785, PMCID: PMC7735158, DOI: 10.1182/blood.2020006321.
- Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice.Xavier-Ferrucio J, Scanlon V, Li X, Zhang PX, Lozovatsky L, Ayala-Lopez N, Tebaldi T, Halene S, Cao C, Fleming MD, Finberg KE, Krause DS. Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice. Blood 2019, 134: 1547-1557. PMID: 31439541, PMCID: PMC6839952, DOI: 10.1182/blood.2019002039.
- Genetic loss of Tmprss6 alters terminal erythroid differentiation in a mouse model of β-thalassemia intermediaStagg DB, Whittlesey RL, Li X, Lozovatsky L, Gardenghi S, Rivella S, Finberg KE. Genetic loss of Tmprss6 alters terminal erythroid differentiation in a mouse model of β-thalassemia intermedia Haematologica 2019, 104: e442-e446. PMID: 30819909, PMCID: PMC6886429, DOI: 10.3324/haematol.2018.213371.
- Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)Finberg KE, Heeney MM, Campagna DR, Aydınok 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) Nature Genetics 2008, 40: 569-571. PMID: 18408718, PMCID: PMC3104019, DOI: 10.1038/ng.130.
- Blocking (iron) traffic in the gutFinberg KE. Blocking (iron) traffic in the gut Blood 2022, 139: 2424-2425. PMID: 35446376, DOI: 10.1182/blood.2022015480.
- Yale Precision Medicine Tumor Board: reawakening the guardian of the genomeGrant MJ, Finberg KE, Walther Z, Stein SM, Lacy J, Eder JP, Goldberg SB. Yale Precision Medicine Tumor Board: reawakening the guardian of the genome The Lancet Oncology 2022, 23: 337-338. PMID: 35240081, DOI: 10.1016/s1470-2045(22)00037-7.
- Yale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment planGibson JA, Finberg KE, Nalbantoglu I, Cecchini M, Ganzak A, Walther Z, Sklar JL, Eder JP, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment plan The Lancet Oncology 2021, 22: 306-307. PMID: 33662283, DOI: 10.1016/s1470-2045(20)30683-5.
- Ironing out an approach to alleviate the hypoferremia of acute inflammationFinberg KE. Ironing out an approach to alleviate the hypoferremia of acute inflammation Haematologica 2021, 106: 326-328. PMID: 33522782, PMCID: PMC7849331, DOI: 10.3324/haematol.2020.266627.
- 12 Iron Metabolism and Related DisordersGinzburg Y, Finberg K. 12 Iron Metabolism and Related Disorders 2021, 445-499. DOI: 10.1016/b978-0-12-812535-9.00012-1.
- Functional characterization of a novel SLC40A1 Arg88Ile mutation in a kindred with familial iron overload treated by phlebotomyWomack J, Sukumaran A, Li X, Lozovatsky L, Gallagher PG, Seid JE, Finberg KE. Functional characterization of a novel SLC40A1 Arg88Ile mutation in a kindred with familial iron overload treated by phlebotomy Blood Cells Molecules And Diseases 2020, 87: 102532. PMID: 33385755, PMCID: PMC8272917, DOI: 10.1016/j.bcmd.2020.102532.
- Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testingHafez N, Walther Z, Eder JP, Sklar JL, Gettinger SN, Finberg KE, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testing The Lancet Oncology 2020, 21: 343-344. PMID: 32950226, DOI: 10.1016/s1470-2045(20)30010-3.
- Going solo in iron transport.Finberg KE. Going solo in iron transport. Blood 2019, 134: 1363-1364. PMID: 31698431, DOI: 10.1182/blood.2019003019.
- Yale Cancer Center Precision Medicine Tumor Board: one tumour, multiple targetsStewart T, Finberg K, Walther Z, Sklar JL, Hafez N, Eder JP, Anderson K, Wilson F, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: one tumour, multiple targets The Lancet Oncology 2018, 19: 1567-1568. PMID: 32956641, DOI: 10.1016/s1470-2045(18)30759-9.
- Ironing out the role of Toll-like receptorsFinberg KE. Ironing out the role of Toll-like receptors Blood 2015, 125: 2183-2184. PMID: 25838278, DOI: 10.1182/blood-2015-02-628412.
- Iron-Refractory Iron Deficiency Anemia (IRIDA)Heeney MM, Finberg KE. Iron-Refractory Iron Deficiency Anemia (IRIDA) Hematology/Oncology Clinics Of North America 2014, 28: 637-652. PMID: 25064705, DOI: 10.1016/j.hoc.2014.04.009.
- Regulation of systemic iron homeostasisFinberg KE. Regulation of systemic iron homeostasis Current Opinion In Hematology 2013, 20: 208-214. PMID: 23426198, DOI: 10.1097/moh.0b013e32835f5a47.
- Striking the target in iron overload disordersFinberg KE. Striking the target in iron overload disorders Journal Of Clinical Investigation 2013, 123: 1424-1427. PMID: 23524962, PMCID: PMC3613936, DOI: 10.1172/jci68889.
- Iron Refractory Iron Deficiency Anemia: Presentation With Hyperferritinemia and Response to Oral Iron TherapyKhuong-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, 131: e620-e625. PMID: 23319530, PMCID: PMC3675830, DOI: 10.1542/peds.2012-1303.
- Unraveling Mechanisms Regulating Systemic Iron HomeostasisFinberg KE. Unraveling Mechanisms Regulating Systemic Iron Homeostasis Hematology 2011, 2011: 532-537. PMID: 22160085, PMCID: PMC3648641, DOI: 10.1182/asheducation-2011.1.532.
- Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in miceFinberg KE, Whittlesey RL, Andrews NC. Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice Blood 2011, 117: 4590-4599. PMID: 21355094, PMCID: PMC3099575, DOI: 10.1182/blood-2010-10-315507.
- Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasisFinberg 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, 115: 3817-3826. PMID: 20200349, PMCID: PMC2865872, DOI: 10.1182/blood-2009-05-224808.
- Iron-Refractory Iron Deficiency AnemiaFinberg KE. Iron-Refractory Iron Deficiency Anemia Seminars In Hematology 2009, 46: 378-386. PMID: 19786206, DOI: 10.1053/j.seminhematol.2009.06.006.
- Iron homeostasis: casting new rolesFinberg KE. Iron homeostasis: casting new roles Blood 2008, 112: 2181-2181. PMID: 18779402, DOI: 10.1182/blood-2008-06-164327.