Soluble Transferrin Receptor

Background

The soluble transferrin receptor (sTfR) is a significant biomarker utilized in the assessment of the body’s iron status and the rate of erythropoiesis, which is the process of red blood cell production. It offers a unique window into the cellular demand for iron, providing insights into various conditions affecting iron metabolism and the formation of red blood cells.

Biological Basis

Iron is an indispensable mineral required for numerous biological functions, most notably for oxygen transport as a component of hemoglobin. Iron circulates in the bloodstream bound to transferrin, a transport protein. Cells acquire iron by internalizing transferrin that is bound to iron via specific cell surface proteins known as transferrin receptors, primarily transferrin receptor 1 (TFR1). When cells, particularly those involved in red blood cell production within the bone marrow, experience an increased need for iron, they upregulate the expression ofTFR1 on their surface. A portion of this TFR1 is proteolytically cleaved from the cell membrane and released into the circulation as sTfR. Consequently, the concentration of sTfR in the blood directly reflects the total cellular mass of TFR1 and, by extension, the overall cellular iron demand and the intensity of erythropoietic activity.

Clinical Relevance

The of sTfR holds considerable clinical value, particularly in the diagnosis and differentiation of various forms of anemia. It is especially useful for distinguishing iron deficiency anemia (IDA) from the anemia of chronic disease (ACD). In IDA, the body’s iron stores are depleted, leading to an increased cellular demand for iron and, thus, elevated sTfR levels. Conversely, in ACD, sTfR levels typically remain within the normal range or show only a modest increase, as the anemia is primarily driven by inflammatory processes that sequester iron rather than an absolute cellular iron deficit. This distinction is crucial because conventional iron markers, such as ferritin, can be misleading in inflammatory states, as ferritin itself is an acute phase reactant that can be elevated even when functional iron is scarce. sTfR is less influenced by inflammation, making it a more reliable indicator of functional iron deficiency in complex clinical scenarios. It can also be employed to monitor the efficacy of iron replacement therapies.

Social Importance

Accurate assessment of iron status and timely diagnosis of anemia have broad social implications. Iron deficiency is recognized as the most prevalent nutritional deficiency globally, impacting billions of individuals. It contributes to impaired cognitive development in children, reduced productivity in adults, and increased rates of maternal and child mortality. By offering a robust and less confounded measure of iron status, sTfR facilitates precise diagnosis of iron deficiency, thereby preventing misdiagnosis and the administration of inappropriate treatments. This capability leads to more effective public health interventions, better-targeted iron supplementation programs, and improved health outcomes, particularly for vulnerable populations such as pregnant women and young children. The widespread use of sTfR contributes to optimizing patient care, reducing healthcare costs associated with managing chronic conditions, and ultimately advancing global health equity.

Statistical Interpretation and Study Design

The interpretation of statistical significance and estimated effect sizes for genetic variants influencing soluble transferrin receptor should be approached with caution due to inherent study design complexities. Specifically, reported p-values in some studies were not adjusted for multiple comparisons, which can inflate the number of statistically significant findings and potentially overestimate effect sizes. For instance, genome-wide association studies (GWAS) with 100K or 300K markers typically require much more stringent significance thresholds, such as 5 x 10^-7 or 1.6 x 10^-7 after Bonferroni correction, to account for the vast number of tests performed.^[1]Without such adjustments, there is an increased risk of false positives, which necessitates independent replication to confirm initial associations and ensure robust conclusions regarding the genetic determinants of soluble transferrin receptor levels.

Incomplete Genetic Architecture and Remaining Knowledge Gaps

Despite identifying significant genetic associations, current research indicates that a substantial portion of the heritability for related iron metabolism traits, such as serum transferrin levels, remains unexplained. For example, variants in genes likeTF and HFEaccount for only approximately 40% of the genetic variation in serum transferrin levels.^[1]This “missing heritability” suggests that many other genetic factors, including rare variants, structural variations, or complex epistatic interactions, are yet to be discovered for soluble transferrin receptor. Furthermore, the role of environmental factors and gene-environment interactions, which are known to influence iron status, are often not fully elucidated, representing a significant knowledge gap in understanding the complete etiology of soluble transferrin receptor variability.

Phenotypic Specificity and Generalizability

A key limitation arises from the specificity of the phenotypes studied and the generalizability of findings across diverse populations. While insights into serum transferrin levels provide valuable context, the direct genetic architecture of soluble transferrin receptor may differ, and variants identified for one may not fully capture the genetic influences on the other. Moreover, some findings are based on cohorts primarily of European ancestry, as indicated by the use of HapMap CEU data for linkage disequilibrium analysis.^[1] This raises concerns about the generalizability of identified genetic associations and effect sizes to populations with different ancestral backgrounds, where allele frequencies, linkage disequilibrium patterns, and environmental exposures can vary significantly, potentially impacting the clinical utility of these genetic markers.

Variants

Genetic variations play a crucial role in determining an individual’s iron status and the levels of soluble transferrin receptor (sTfR), a key biomarker reflecting the body’s iron stores and erythropoietic activity. ThePCSK7 (Proprotein Convertase Subtilisin/Kexin Type 7) gene, for instance, encodes an enzyme involved in processing various precursor proteins, influencing their maturation and activity. Variants within this gene, including rs11216316 , rs236918 , and rs2238005 , can impact the production or shedding of proteins important for cellular function, with rs236918 showing a strong association with sTfR levels, and this association remains significant even when transferrin saturation is considered.^[2] The TMPRSS6gene encodes matriptase-2, an enzyme critical for regulating iron absorption through its influence on hepcidin, the master hormone of iron homeostasis, and variants likers855791 are known to affect these pathways, thereby impacting iron stores and sTfR. The HFE gene, notably through its rs1800562 (C282Y) variant, is central to systemic iron regulation, interacting with the transferrin receptor to control cellular iron uptake, and variations inHFEsignificantly contribute to genetic differences in serum-transferrin levels.^[1] Furthermore, TFRC(Transferrin Receptor) directly encodes transferrin receptor 1, the protein vital for cellular iron import, and its soluble form is released into the bloodstream, making variants such asrs112856048 directly relevant to sTfR levels and overall iron status.

Genetic variants located in intergenic regions can influence the expression or regulation of neighboring genes, which may indirectly affect cellular metabolism or protein trafficking relevant to iron homeostasis. For instance, rs116816795 is found between GNPDA1 (involved in amino sugar metabolism) and NDFIP1 (playing a role in protein degradation), processes that broadly influence cell function and could subtly modulate pathways affecting sTfR. Similarly, rs72832593 is situated between SLC17A2(a phosphate transporter) andTRIM38 (a protein involved in ubiquitination and immunity), suggesting potential influences on transport mechanisms or immune responses that can interact with iron metabolism. The variant rs115094736 resides within a region encompassing CFHR1 and CFHR4, genes integral to the complement system, a key component of innate immunity; inflammatory states, often mediated by the complement system, are known to significantly alter iron metabolism and can affect sTfR levels.^[2] Another intergenic variant, rs10047462 , near APOA1-AS (an antisense RNA) and SIK3 (Salt-Inducible Kinase 3), could impact metabolic signaling pathways, as SIK3 is involved in various cellular stress and metabolic responses. These genetic variations highlight the complex interplay of diverse cellular and systemic pathways in determining iron-related traits.^[1] Variations within genes involved in inflammation and hematopoiesis also play a role in influencing sTfR levels. PAFAH1B2(Platelet-Activating Factor Acetylhydrolase 1b, Catalytic Subunit 2), for example, has variants likers187669805 , rs7112513 , and rs7940310 that are relevant due to the gene’s function in inactivating platelet-activating factor, a potent mediator of inflammation. Chronic inflammation can significantly impact iron homeostasis, often leading to altered iron utilization and changes in sTfR levels. TheIKZF1 gene (IKAROS Family Zinc Finger 1) encodes a critical transcription factor essential for the development and maturation of lymphocytes and other hematopoietic cells. Given its fundamental role in blood cell formation, variants such as rs6592965 in IKZF1 could influence erythropoiesis and the body’s iron utilization, thereby potentially affecting sTfR, which reflects both iron stores and erythropoietic activity. These genetic insights collectively underscore the multifaceted nature of iron regulation and its widespread implications for health.^{[1], [2]}

Key Variants

RS ID	Gene	Related Traits
rs11216316 rs236918 rs2238005	PCSK7	soluble transferrin receptor
rs855791	TMPRSS6	mean corpuscular hemoglobin iron biomarker , ferritin iron biomarker , transferrin saturation iron biomarker , serum iron amount iron biomarker , transferrin
rs1800562	H2BC4, HFE	iron biomarker , ferritin iron biomarker , transferrin saturation iron biomarker , serum iron amount iron biomarker , transferrin hematocrit
rs116816795	GNPDA1 - NDFIP1	soluble transferrin receptor
rs112856048	TFRC	soluble transferrin receptor
rs72832593	SLC17A2 - TRIM38	soluble transferrin receptor
rs115094736	CFHR1 - CFHR4	soluble transferrin receptor
rs10047462	APOA1-AS, SIK3	soluble transferrin receptor sphingomyelin triglyceride low density lipoprotein cholesterol degree of unsaturation
rs187669805 rs7112513 rs7940310	PAFAH1B2	soluble transferrin receptor
rs6592965	IKZF1	erythrocyte volume erythrocyte count mean corpuscular hemoglobin reticulocyte count platelet count

Advanced Proteomic Platforms for Biomarker Identification

The diagnosis of conditions utilizing soluble transferrin receptor relies heavily on advanced proteomic technologies capable of precisely quantifying plasma proteins. Multiplexed, aptamer-based approaches, such as the SOMAscan assay, enable the simultaneous of thousands of plasma proteins, including potential biomarkers like soluble transferrin receptor.^[3] This methodology offers a significant advantage over conventional immunoassays by extending the lower limit of detectable protein abundance, thereby allowing for the detection of both extracellular and intracellular proteins, even those present in low concentrations.^[3] Such comprehensive protein profiling is instrumental in identifying proteins implicated in the pathophysiology of various human diseases, providing a broad foundation for diagnostic evaluation and biomarker discovery.^[3]

Quantitative Analysis and Assay Validation

The reliability of soluble transferrin receptor as a diagnostic tool is underscored by rigorous quantitative analysis and assay validation. High-throughput protein platforms exhibit robust performance characteristics, including consistent coefficients of variation for analyses, which for similar soluble proteins typically range from 4.5% to 6.2%, ensuring high reproducibility across measurements.^[4] Attention is also given to the accurate quantification of proteins across a wide dynamic range, with methods in place to handle levels that fall below or exceed assay detection limits, thus minimizing data loss and maximizing the utility of the collected proteomic data.^[5] These technical assurances are fundamental for generating accurate and dependable results essential for clinical decision-making.

Clinical Relevance of Soluble Plasma Protein Biomarkers

While specific clinical criteria for soluble transferrin receptor are not detailed in the researchs, the general clinical utility of measuring plasma proteins for diagnostic purposes is well-established. The selection of proteins for these advanced platforms focuses on those suspected to be involved in the pathophysiology of human disease, indicating their potential as diagnostic or prognostic indicators.^[3]By accurately quantifying these circulating biomarkers, clinicians can gain insights into disease states, monitor progression, or assess treatment responses, thereby contributing to a more precise clinical evaluation. The ability to measure a wide array of proteins allows for a more holistic view of physiological and pathological processes, guiding diagnostic strategies in complex conditions.

The Role of Transferrin in Iron Transport

Transferrin (TF) is a critical protein within the human body, primarily responsible for the vital transport of iron through the bloodstream. This circulating protein ensures that iron, an essential mineral, is delivered to various tissues and cells where it is needed for numerous biological processes, such as oxygen transport, cellular respiration, and DNA synthesis. The maintenance of appropriate serum transferrin levels is crucial for systemic iron homeostasis, preventing both the detrimental effects of iron deficiency and the toxicity of iron overload throughout the body.

Molecular Pathways Governing Transferrin Secretion

The synthesis and subsequent secretion of serum transferrin involve intricate molecular and cellular pathways. Proteins destined for secretion, such as serum transferrin, are processed through the endoplasmic reticulum and Golgi apparatus, a pathway that relies on specific cellular machinery for accurate targeting. A key component of this machinery is the signal-recognition particle receptor, which is encoded by theSRPRB gene. This receptor plays an essential role in guiding newly synthesized secreted proteins to their proper cellular compartments for processing and eventual release into the circulatory system.^[1]The efficiency of this protein targeting mechanism directly impacts the quantity of transferrin available in the serum.

Genetic Determinants of Serum Transferrin Levels

Genetic factors significantly influence the circulating levels of serum transferrin. Variations within theTFgene itself, which codes for transferrin, and theHFEgene, a gene known to play a role in iron metabolism, together account for a substantial portion (approximately 40%) of the inherited differences observed in serum transferrin concentrations among individuals.^[1] Beyond these primary genes, genetic variations in the SRPRBgene also contribute to the regulation of serum transferrin. Specifically, certain single nucleotide polymorphisms (SNPs) withinSRPRB, such as rs10512913 , have been associated with both the expression levels of SRPRBmRNA and the concentration of serum transferrin.^[1] These observations suggest a potential causative relationship where genetic variations in SRPRBtranscripts can modulate the amount of serum transferrin.

Regulation of Transferrin Receptor Expression and Shedding

The concentration of soluble transferrin receptor (sTfR) in circulation is a dynamic reflection of cellular transferrin receptor 1 (TfR1) expression and its subsequent proteolytic cleavage from the cell surface. This intricate process is tightly controlled at multiple levels, encompassing both gene regulation and post-translational modifications. For instance, the release of sTfR is directly regulated by the binding of its ligand, ferritransferrin, indicating an allosteric control mechanism where ligand occupancy influences receptor conformation and susceptibility to shedding.^[6] The shedding itself is constitutively mediated by an integral membrane metalloprotease, an enzyme sensitive to inhibitors like tumor necrosis factor alpha protease inhibitor-2, highlighting a specific protein modification pathway responsible for generating the soluble form.^[7] Furthermore, studies have identified that the protein TTPspecifically regulates the internalization of the transferrin receptor, adding another layer of post-translational control over the surface availability ofTfR1 and, consequently, the pool from which sTfR can be generated.^[8] Genetic factors also play a significant role in modulating sTfR levels by influencing the expression or function of key components within the iron metabolism machinery. Common variants in genes such as TMPRSS6 have been associated with both iron status and erythrocyte volume, suggesting an indirect regulatory impact on TfR1 expression and sTfR release.^[9] Similarly, a novel association has been found between the proprotein convertase PCSK7 gene locus and sTfR levels.^[2] Proprotein convertases, including PCSK7, are known to regulate the processing and activity of prohepcidin, a central regulator of iron, thereby indirectly affecting TfR1 expression through systemic iron feedback loops.^[2] These regulatory mechanisms collectively ensure that sTfR levels accurately reflect cellular iron demand and the rate of TfR1 turnover.

Iron Sensing and Systemic Signaling Cascades

The body maintains systemic iron homeostasis through complex signaling pathways that respond to iron levels, with sTfR serving as a key indicator of cellular iron demand. A crucial component in this network is transferrin receptor 2 (TfR2), a member of the transferrin receptor-like family.^[10] TfR2interacts with diferric transferrin, and this interaction is critical for its role in iron sensing, particularly in hepatocytes.^[11]This receptor activation initiates intracellular signaling cascades that contribute to the regulation of hepcidin, the master hormone of iron metabolism. Hepcidin synthesis, primarily in the liver, is upregulated by high iron levels and downregulated by iron deficiency, creating a vital feedback loop.

TfR2 works in concert with other iron sensors, such as HFEand hemojuvelin (HJV), to activate the BMP/SMADsignaling pathway, which ultimately controls hepcidin transcription. Genetic variants inTFR2 have been implicated in the physiological regulation of serum iron levels, underscoring its importance in this signaling cascade.^[12] Another significant regulator is TMPRSS6(also known as matriptase-2), a serine protease that inhibits hepcidin activation by cleaving membrane hemojuvelin.^[13]By modulating hepcidin, these pathways dictate the availability of iron for cellular processes, which in turn influencesTfR1 expression and subsequent sTfR generation, thus integrating systemic iron signaling with cellular iron uptake mechanisms.^[14]

Metabolic Integration and Erythropoietic Demand

Soluble transferrin receptor levels are deeply integrated with metabolic pathways, particularly those governing iron utilization and erythropoiesis, the process of red blood cell formation. As a truncated form ofTfR1, sTfR reflects the total cellular pool of TfR1, which is highly expressed on erythroid progenitor cells to facilitate the massive iron uptake required for hemoglobin synthesis.^[15] Therefore, an elevated sTfR concentration often signifies increased erythropoietic activity or heightened cellular iron demand, such as during periods of rapid red blood cell production or in situations of iron deficiency where cells upregulate TfR1 to maximize iron acquisition. This makes sTfR a valuable marker for assessing the functional iron status and the intensity of erythropoiesis.

The interplay between iron metabolism and broader energy metabolism is also evident, as efficient iron handling is essential for cellular respiration and energy production. Any disruption in iron flux, whether due to inadequate intake, impaired absorption, or chronic blood loss, directly impacts erythroid cell proliferation and maturation, leading to increased TfR1 expression and consequently higher sTfR levels. This metabolic regulation ensures that cells can adapt their iron uptake capacity to meet fluctuating demands, with sTfR acting as a measurable biomarker reflecting this adaptive response. Variants in genes like TF and HFEinfluence serum transferrin levels, which in turn affect iron availability forTfR1 mediated uptake, further illustrating the interconnectedness of these metabolic pathways.^[9]

Pathophysiological Implications and Disease Mechanisms

Dysregulation within the pathways governing transferrin receptor expression and iron homeostasis leads to various disease-relevant mechanisms, with sTfR levels serving as a crucial diagnostic and monitoring tool. In conditions of iron deficiency, for instance, cells upregulateTfR1 to compensate for reduced iron availability, resulting in a pronounced increase in sTfR concentrations in the blood.^[15]This compensatory mechanism highlights the body’s attempt to maintain iron supply to vital processes like erythropoiesis despite systemic scarcity. Conversely, in iron overload disorders, or conditions where iron utilization is impaired despite adequate stores (e.g., anemia of chronic disease),TfR1 expression may be suppressed or unresponsive, leading to differing sTfR patterns that aid in differential diagnosis.

The intricate crosstalk between iron metabolism and inflammatory pathways also influences sTfR levels, as inflammation can alter iron distribution and erythropoiesis. Cytokines released during inflammation can induce hepcidin production, leading to iron sequestration and functional iron deficiency, which may then indirectly affectTfR1expression. Understanding these disease-relevant mechanisms, including pathway dysregulation and compensatory responses, is vital for identifying potential therapeutic targets. For example, modulating the activity of proteases involved inTfR1 shedding or targeting specific components of the iron sensing machinery, such as TFR2 or TMPRSS6, could offer novel strategies for managing iron-related disorders.^[13]

Frequently Asked Questions About Soluble Transferrin Receptor

These questions address the most important and specific aspects of soluble transferrin receptor based on current genetic research.

---

1. Why do I feel tired if my regular iron test looks normal?

Your “regular” iron test, like ferritin, can be misleading if you have inflammation from another health issue. In these cases, ferritin levels might look normal or even high, even if your body actually has an iron shortage. A soluble transferrin receptor (sTfR) test gives a clearer picture because it’s less affected by inflammation, showing if your cells truly need more iron.

2. I eat healthy, but always feel run down; could my iron be the problem?

Yes, absolutely. Even with a healthy diet, you might not be absorbing iron efficiently, or your body’s demand could be very high for other reasons. Feeling run down is a classic symptom of iron deficiency. Measuring soluble transferrin receptor (sTfR) can confirm if your cells are truly hungry for iron, helping your doctor find the right solution.

3. My parents and I both have iron issues. Is that just a coincidence?

It’s likely not a coincidence; your genes play a significant role in how your body handles iron. Variations in genes like HFE, TMPRSS6, or PCSK7can affect everything from iron absorption to how your cells use iron, impacting your overall iron status and levels of soluble transferrin receptor. This can make certain individuals, and families, more prone to iron imbalances.

4. How does my doctor know if my iron supplements are actually working?

Your doctor can monitor your soluble transferrin receptor (sTfR) levels. As your body responds to iron supplements and your iron stores improve, your cells’ demand for iron decreases. This will cause your sTfR levels in the blood to go down, indicating that the treatment is effectively replenishing your iron and helping your body produce red blood cells.

5. Does my ethnic background change how my iron levels are understood?

Yes, it can. Many studies identifying genetic factors for iron levels, including soluble transferrin receptor, have primarily focused on populations of European ancestry. This means that genetic associations and typical ranges might differ in people from other backgrounds due to variations in allele frequencies and environmental exposures. It’s important for doctors to consider your specific ethnic background when interpreting your results.

6. If I get a genetic test for iron, will it tell me everything?

Not everything, unfortunately. While genetic tests can identify important variants in genes like HFE or TMPRSS6that affect iron metabolism, they don’t capture the full picture. A significant portion of how iron levels are inherited is still unknown, and environmental factors like diet, lifestyle, and interactions between different genes also play a big role.

7. If I have an ongoing illness, can my iron levels still be accurately measured?

Yes, with the right test. Chronic illnesses often cause inflammation, which can skew traditional iron tests like ferritin, making them appear normal or even high despite a real iron shortage. However, measuring soluble transferrin receptor (sTfR) is much less affected by inflammation, providing a more accurate and reliable assessment of your true iron status even when you have an ongoing illness.

8. Why would my body suddenly need more iron than usual?

Your body’s demand for iron goes up significantly when it’s making more red blood cells, a process called erythropoiesis. This increased production, perhaps due to blood loss or certain medical conditions, means your cells need more iron to build hemoglobin. This higher cellular demand is directly reflected by increased levels of soluble transferrin receptor in your blood.

9. Why is getting my iron levels right so important for my kids’ future?

Ensuring proper iron levels, especially in children, is crucial because iron deficiency can severely impair cognitive development, reduce learning ability, and lower energy levels. For pregnant women, it’s vital for healthy fetal development. Accurate diagnosis using tests like soluble transferrin receptor helps target treatments effectively, preventing long-term health and developmental problems that can affect their entire lives.

10. Can my daily habits really impact how my body uses iron?

Absolutely. While your genes certainly play a role in how your body processes iron, your daily habits and environment have a significant impact too. Things like your diet, specific nutrient intake, and overall lifestyle can interact with your genetic predispositions, influencing how well you absorb iron, your cellular iron demand, and ultimately your overall iron status.

---

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Benyamin B, et al. “Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.” Am J Hum Genet, vol. 83, no. 6, 2008, pp. 696-701.

[2] Oexle, K. et al. “Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels.”Human Molecular Genetics, vol. 20, 2011.

[3] Sun, BB, et al. “Genomic atlas of the human plasma proteome.” Nature, vol. 558, no. 7708, 2018, pp. 73-79.

[4] Qi, L, et al. “Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes.” Hum Mol Genet, vol. 19, no. 10, 2010, pp. 1979-85.

[5] Melzer, D, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, vol. 4, no. 5, 2008, p. e1000072.

[6] Dassler, K., Zydek, M., Wandzik, K., Kaup, M., and Fuchs, H. “Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin.”J. Biol. Chem., vol. 281, 2006, pp. 3297–3304.

[7] Kaup, M., Dassler, K., Weise, C., and Fuchs, H. “Shedding of the transferrin receptor is mediated constitutively by an integral membrane metalloprotease sensitive to tumor necrosis factor alpha protease inhibitor-2.”J. Biol. Chem., vol. 277, 2002, pp. 38494–38502.

[8] Tosoni, D., Puri, C., Confalonieri, S., Salcini, A.E., De Camilli, P., Tacchetti, C., and Di Fiore, P.P. “TTPspecifically regulates the internalization of the transferrin receptor.”Cell, vol. 123, 2005, pp. 875–888.

[9] Benyamin, B., et al. “Variants in TF and HFE Explain Approximately 40% of Genetic Variation in Serum-Transferrin Levels.”American Journal of Human Genetics, vol. 84, no. 1, 2009, pp. 119-27.

[10] Kawabata, H., Yang, R., Hirama, T., Vuong, P.T., Kawano, S., Gombart, A.F., and Koeffler, H.P. “Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family.”J. Biol. Chem., vol. 274, 1999, pp. 20826–20832.

[11] Ikuta, K., Yersin, A., Ikai, A., Aisen, P., and Kohgo, Y. “Characterization of the interaction between diferric transferrin and transferrin receptor 2 by functional assays and atomic force microscopy.”J. Mol. Biol., vol. 397, 2010, pp. 375–384.

[12] Pichler, I., et al. “Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.” Hum Mol Genet, 2012.

[13] Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., et al. “The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.”Cell Metab, vol. 8, 2008, pp. 502–511.

[14] Hentze, M.W., Muckenthaler, M.U., Galy, B., and Camaschella, C. “Two to tango: regulation of Mammalian iron metabolism.” Cell, vol. 142, 2010.

[15] Skikne, B.S. “Serum transferrin receptor.”Am. J. Hematol., vol. 83, 2008.