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Karin Finberg, MD, PhD

Associate Professor of Pathology
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Additional Titles

Enrichment Core Director, Yale Cooperative Center of Excellence in Hematology

Course Director, HSCI 9100 Molecular Genomic Pathology in Precision Medicine, Masters of Health Sciences Program Clinical Investigation Track

Associate Director, Molecular Genetic Pathology Fellowship Program

Associate Clinical Director, Tumor Profiling Laboratory

Co-Director, Yale Summer Enrichment Research Experience , Yale Center for Clinical Investigation (YCCI)

About

Titles

Associate Professor of Pathology

Enrichment Core Director, Yale Cooperative Center of Excellence in Hematology; Course Director, HSCI 9100 Molecular Genomic Pathology in Precision Medicine, Masters of Health Sciences Program Clinical Investigation Track; Associate Director, Molecular Genetic Pathology Fellowship Program; Associate Clinical Director, Tumor Profiling Laboratory; Co-Director, Yale Summer Enrichment Research Experience , Yale Center for Clinical Investigation (YCCI)

Biography

Karin Finberg received her B.S., M.D., and Ph.D. degrees from Yale. Her Ph.D. dissertation with Dr. Richard Lifton in the Department of Genetics focused on the genetic basis of an autosomal recessive disorder of systemic pH homeostasis, distal renal tubular acidosis with sensorineural deafness. After graduating from Yale, Karin completed residency training in Clinical Pathology at Massachusetts General Hospital and clinical fellowship training in the Harvard Medical School Molecular Genetic Pathology Training Program based at Brigham and Women’s Hospital. She then completed postdoctoral research training in the laboratory of Dr. Nancy Andrews, first at Children’s Hospital Boston and later at Duke University Medical Center, where she employed genetic study of patients with an inherited form of iron deficiency anemia to shed insight into mechanisms of systemic iron regulation. In her research laboratory at Yale, Karin continues to investigate mechanisms of iron balance through genetic study of patients with iron-related phenotypes and through characterization of genetically targeted mouse models. She also contributes to patient care as a molecular genetic pathologist in the Molecular Diagnostics Unit of the Department of Pathology.

Appointments

Education & Training

Medical Instructor
Duke University Medical Center (2013)
Sr Research Associate
Duke University Medical Center (2009)
Research Fellow
Children’s Hospital Boston (2008)
Resident
Massachusetts General Hospital (2007)
Clinical Fellow
Brigham and Women's Hospital (2006)
Resident
Massachusetts General Hospital (2005)
MD
Yale School of Medicine (2003)
PhD
Yale School of Medicine, Genetics (2002)
BS
Yale College, Biology (1993)

Research

Overview

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.

Defining novel mechanisms mediating the mobilization of the iron stores from liver

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.



Medical Subject Headings (MeSH)

Anemia, Iron-Deficiency; Blood; Blood Cells; Genetic Diseases, Inborn; Hematologic Diseases; Hematopoiesis; Hemochromatosis; Liver Diseases

Research at a Glance

Yale Co-Authors

Frequent collaborators of Karin Finberg's published research.

Publications

Featured Publications

2023

2022

Academic Achievements & Community Involvement

  • activity

    Yale School of Medicine MD/PhD Faculty Committee

  • activity

    International BioIron Society

  • activity

    American Society of Hematology Scientific Committee on Iron and Heme

  • activity

    Blood, Editorial Board

  • honor

    Gunshin-Levy Young Investigator Award

Clinical Care

Overview

Karin Finberg, MD, PhD, is a board-certified molecular genetic pathologist who specializes in using genetic sequencing techniques to characterize tumors from patients with cancer. Her clinical activities are performed in Yale New Haven Hospital's (YNHH) Tumor Profiling Laboratory.

“Our laboratory performs genetic analyses on a wide range of solid tumor types, including lung cancer, colorectal cancer, melanoma, and many others,” Dr. Finberg says. “In some cases, we are looking for specific genetic alterations in the tumor DNA that could make a patient eligible for a selected FDA-approved therapy that targets a particular genetic change. In other cases, we are evaluating the tumor DNA and RNA for a broader range of genetic abnormalities that might serve as entry criteria for clinical trials evaluating drugs that are being actively investigated.”

Dr. Finberg’s role is to review tumor testing results and to provide a clinical interpretation that will aid the referring oncologist in planning therapy for the patient. In addition to preparing pathology reports, she discusses tumor testing results with oncologists at the Yale Cancer Center's Precision Medicine Tumor Board, where molecular findings are considered in the context of each patient's individual clinical picture to help determine therapeutic options.

"There has been steady progress in the development of targeted therapies in recent years, and as a result, we have seen a large increase in tumor testing requests placed by oncologists," Dr. Finberg says. “By looking for a wide range of genetic changes in tumor specimens, we hope to increase our ability to match a patient to a clinical trial.”

Dr. Finberg divides her time between clinical work in the YNHH Tumor Profiling Laboratory and genetic-based laboratory research that investigates how the body handles iron, a metal that is essential for growth of normal cells, as well as for cancer cells.

At Yale School of Medicine, Dr. Finberg is an associate professor of pathology.

Clinical Specialties

Pathology; Molecular & Genomic Pathology

Fact Sheets

Board Certifications

  • Molecular Genetic Pathology

    Certification Organization
    AB of Pathology
    Original Certification Date
    2007
  • Clinical Pathology

    Certification Organization
    AB of Pathology
    Original Certification Date
    2007

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Nov 20248Friday
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