Alphabetized Annotated Bibliography
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Adams, P. C.; Barton, J. C. How I Treat Hemochromatosis. Blood 2010, 116 (3), 317–325.
https://ashpublications.org/blood/article/116/3/317/27584/How-I-treat-hemochromatosis
This article provides detailed information on ways to treat hemochromatosis.
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Aisen, P. Transferrin Receptor 1. The International Journal of Biochemistry & Cell Biology 2004, 36 (11), 2137–2143.
https://www.sciencedirect.com/science/article/pii/S1357272504000615?casa_token=U1wLc80IIicAAAAA:iXFOfg85Cm1_qWSvmxKPByNVE6fbaq9oZXT2Ikvyd3LwoboNQ8WWGam7uhsgPBrwoLIwN5-jt7M
This paper provides information on the specific functions and structure of transferrin receptor 1.
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Altamura, S.; Schaeper, U.; Dames, S.; Löffler, K.; Eisermann, M.; Frauendorf, C.; Müdder, K.; Neves, J.; Muckenthaler, M. U. SLN124, a GalNAc-SiRNA Conjugate Targeting TMPRSS6, Efficiently Prevents Iron Overload in Hereditary Haemochromatosis Type 1. Hemasphere 2019, 3 (6).
https://journals.lww.com/hemasphere/Fulltext/2019/12000/SLN124,_a_GalNAc_siRNA_Conjugate_Targeting.18.aspx
This letter verifies that hepcidin is the malfunctioning protein in hemochromatosis type I by targeting Tmprss6 expression, since restoring the gene restores hepcidin levels and decreases iron content. This experiment was done by targeting the gene with SLN124, a GalNAc-siRNA conjugate.
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Bacon, B. R. Hemochromatosis: Diagnosis and Management. Gastroenterology 2001, 120 (3), 718–725.
https://pubmed.ncbi.nlm.nih.gov/11179246/
This article provides information on the iron absorption levels of each mutation seen in hereditary hemochromatosis.
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Bacon, B. R.; Adams, P. C.; Kowdley, K. V.; Powell, L. W.; Tavill, A. S. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology 2011, 54 (1), 328–343.
https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.24330
This article provides information about diagnosing and managing hereditary hemochromatosis.
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Barton, J. C.; Edwards, C. Q. HFE Hemochromatosis. In GeneReviews®; Adam, M. P., Ardinger, H. H., Pagon, R. A., Wallace, S. E., Bean, L. J., Stephens, K., Amemiya, A., Eds.; University of Washington, Seattle: Seattle (WA), 1993.
https://www.ncbi.nlm.nih.gov/pubmed/20301613
This article provides information on how to diagnose and treat hemochromatosis. Specific tests for diagnosis and characteristics of the disease are explained.
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Barton, J. C.; Edwards, C. Q.; Acton, R. T. HFE Gene: Structure, Function, Mutations, and Associated Iron Abnormalities. Gene 2015, 574 (2), 179–192.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660136/
This article describes the HFE gene and HFE protein in detail.
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Bennett, M. J.; Lebrón, J. A.; Bjorkman, P. J. Crystal Structure of the Hereditary Haemochromatosis Protein HFE Complexed with Transferrin Receptor. Nature 2000, 403 (6765), 46–53.
https://www.nature.com/articles/47417
This paper identifies the protein that is affected in hemochromatosis – the HFE protein complexed with the transferrin receptor. Both the uncomplexed and complexed crystal structure of the HFE protein is observed and explained.
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Brissot, P.; Troadec, M.-B.; Bardou-Jacquet, E.; Lan, C. L.; Jouanolle, A.-M.; Deugnier, Y.; Loréal, O. Current Approach to Hemochromatosis. Blood Reviews 2008, 22 (4), 195–210.
https://www.sciencedirect.com/science/article/pii/S0268960X08000209?casa_token=R09gOM2QKA4AAAAA:gGhP_or1uxVMRhsHl3ylTauV9jiCieyvDYXSRcThS2ggzKgltCFq5IWs98A1xGWBrwW2Mm0hZkQ
This paper elaborates on all of the existing types of hereditary hemochromatosis.
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Brissot, P.; Pietrangelo, A.; Adams, P. C.; de Graaff, B.; McLaren, C. E.; Loréal, O. Haemochromatosis. Nature Reviews Disease Primers 2018, 4 (1), 1–15.
https://www.nature.com/articles/nrdp201816
This paper provides a general idea of the effects of the mutations of hereditary hemochromatosis. Diagnoses and treatment options are also discussed.
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Bulaj, Z. J.; Griffen, L. M.; Jorde, L. B.; Edwards, C. Q.; Kushner, J. P. Clinical and Biochemical Abnormalities in People Heterozygous for Hemochromatosis. New England Journal of Medicine 1996, 335 (24), 1799–1805
https://www.nejm.org/doi/full/10.1056/NEJM199612123352403?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
The authors identified that, at the time, ten percent of whites were heterozygous for the HLA-linked hemochromatosis mutation. They performed an analysis in order to determine the effects of age and sex on the phenotype. The authors determined that iron concentrations and transferrin-saturation were higher in heterozygotes than in normal individuals and were not affected by age.
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Camaschella, C.; Nai, A.; Silvestri, L. Iron Metabolism and Iron Disorders Revisited in the Hepcidin Era. Haematologica 2020.
http://www.haematologica.org/content/early/2020/01/14/haematol.2019.232124
This article highlights the mechanisms followed for iron overload and iron deficiency and the role of hepcidin.
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De Domenico, I.; Ward, D. M.; Kaplan, J. Hepcidin and Ferroportin: The New Players in Iron Metabolism. Semin Liver Dis 2011, 31 (3), 272–279.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706197/
This paper explains the role of hepcidin and ferroportin in iron homeostasis.
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El Jabbour, T.; McHugh, K. E.; Patil, D. T.; Zuo, C.; Koo, B. H.; Kim, S.; Lee, H. Histologic Lesions of Porto-Sinusoidal Vascular Disease Following Phlebotomy in Hemochromatosis. Gastroenterology Res 2020, 13 (1), 32–39.
https://www.gastrores.org/index.php/Gastrores/article/view/1236/1273
The authors utilized the widely known fact that phlebotomies induce a decrease in liver fibrosis in hemochromatosis to show that phlebotomy-induced histologic lesions overlap with porto-sinusoidal vascular disease. The authors found that phlebotomy reduces hepatic iron load and induces histologic lesions of PSVD in patients with an HFE mutation, but the lesions are not indicative of being risk factors for PSVD.
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Feder, J. N., A. Gnirke, W. Thomas, Z. Tsuchihashi, D. A. Ruddy, A. Basava, F. Dormishian, et al. A Novel MHC Class I–like Gene Is Mutated in Patients with Hereditary Haemochromatosis. Nature Genetics 1996, 13 (4): 399–408.
https://www.nature.com/articles/ng0896-399
This paper is the first to identify the HFE gene with the C282Y and H63D mutations.
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Feder, J. N.; Tsuchihashi, Z.; Irrinki, A.; Lee, V. K.; Mapa, F. A.; Morikang, E.; Prass, C. E.; Starnes, S. M.; Wolff, R. K.; Parkkila, S.; Sly, W. S.; Schatzman, R. C. The Hemochromatosis Founder Mutation in HLA-H Disrupts Β2-Microglobulin Interaction and Cell Surface Expression. J. Biol. Chem. 1997, 272 (22), 14025–14028.
https://www.jbc.org/content/272/22/14025.long
This paper verifies how the C282Y mutation disrupts the B2-microglobulin binding with the HFE protein.
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Feder, J. N.; Penny, D. M.; Irrinki, A.; Lee, V. K.; Lebrón, J. A.; Watson, N.; Tsuchihashi, Z.; Sigal, E.; Bjorkman, P. J.; Schatzman, R. C. The Hemochromatosis Gene Product Complexes with the Transferrin Receptor and Lowers Its Affinity for Ligand Binding. Proc Natl Acad Sci U S A 1998, 95 (4), 1472–1477.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC19050/
The authors showed that the HFE protein complexes with the transferrin receptor. The C282Y mutation hinders that complexing mechanism.
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Fleming, R. E.; Britton, R. S.; Waheed, A.; Sly, W. S.; Bacon, B. R. Pathophysiology of Hereditary Hemochromatosis. Semin Liver Dis 2005, 25 (4), 411–419.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587012/
This article discusses the HFE gene and protein affected in hereditary hemochromatosis. Iron absorption and the role of the liver is also elucidated.
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Fleming, R. E.; Ponka, P. Iron Overload in Human Disease. New England Journal of Medicine 2012, 366 (4), 348–359.
https://www.nejm.org/doi/full/10.1056/NEJMra1004967?casa_token=5MNexy4l9voAAAAA:itwNn3Dp1hiSwYEBIFwjkMd2sqCqgQX5Pod51Jy11w2S8dedOMC8Ea3scA8VrPqTYLVdXT-0qm4IliA
In the “iron status” section, the molecular level of hepcidin expression is explained – normal hepcidin expression is a result of BMP-6 interactions stimulating a signal transduction through SMAD proteins, which increases hepcidin transcription.
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Gallego, C. J.; Burt, A.; Sundaresan, A. S.; Ye, Z.; Shaw, C.; Crosslin, D. R.; Crane, P. K.; Fullerton, S. M.; Hansen, K.; Carrell, D.; et al. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the EMERGE Network. The American Journal of Human Genetics 2015, 97 (4), 512–520.
https://www.cell.com/ajhg/fulltext/S0002-9297(15)00330-4
This paper used the eMERGE Network to estimate the diagnostic rate and clinical prevalence of hereditary hemochromatosis with the pathogenic HFE variants, p.Cys282Tyr and p.His63Asp. Differences were seen between male and female p.Cys282Try presence, transferrin saturation, and iron overload.
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Ganz, T.; Nemeth, E. Hepcidin and Iron Homeostasis. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 2012, 1823 (9), 1434–1443.
https://www.sciencedirect.com/science/article/pii/S016748891200016X
This paper explains the different ways hepcidin is regulated and malfunctions, specifically how the deficiency results in hemochromatosis.
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Gao, J.; Chen, J.; Kramer, M.; Tsukamoto, H.; Zhang, A.-S.; Enns, C. A. Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression. Cell Metabolism 2009, 9 (3), 217–227.
https://www.sciencedirect.com/science/article/pii/S1550413109000357
This paper verifies that the HFE/TFR2 complex is necessary for hepcidin production.
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Goswami, T.; Andrews, N. C. Hereditary Hemochromatosis Protein, HFE, Interaction with Transferrin Receptor 2 Suggests a Molecular Mechanism for Mammalian Iron Sensing. J. Biol. Chem. 2006, 281 (39), 28494–28498.
https://www.jbc.org/content/281/39/28494.full
This paper shows that the HFE protein and TRF2 binding is not affected by the C282Y or H63D mutations. Since the protein complex is not directly affected, the authors conclude that the production of hepcidin is manipulated by the mutations in a way that does not affect the overall structure.
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Granick, S. Iron Metabolism and Hemochromatosis. Bull N Y Acad Med 1949, 25 (7), 403–428.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1929866/
This review provides a general explanation for the relationship between hemochromatosis and iron. The author starts off by explaining the types and properties of iron compounds that are present in the body, followed by information on regulation of iron absorption and how these aspects relate to hemochromatosis.
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Hentze, M. W.; Muckenthaler, M. U.; Galy, B.; Camaschella, C. Two to Tango: Regulation of Mammalian Iron Metabolism. Cell 2010, 142 (1), 24–38.
https://www.sciencedirect.com/science/article/pii/S009286741000718X
This paper describes the role of hepcidin in iron overload and iron deficiency.
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Hollerer, I.; Bachmann, A.; Muckenthaler, M. U. Pathophysiological Consequences and Benefits of HFE Mutations: 20 Years of Research. Haematologica 2017, 102 (5), 809–817.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477599/
This paper provides a brief summary of the history and molecular and genetic basis of hemochromatosis. Ways to diagnose and common symptoms are also given, along with positive and negative effects of the mutations.
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Huang, J.; Jones, D.; Luo, B.; Sanderson, M.; Soto, J.; Abel, E. D.; Cooksey, R. C.; McClain, D. A. Iron Overload and Diabetes Risk: A Shift From Glucose to Fatty Acid Oxidation and Increased Hepatic Glucose Production in a Mouse Model of Hereditary Hemochromatosis. Diabetes 2011, 60 (1), 80.
https://diabetes.diabetesjournals.org/content/60/1/80.short
This study examined the glucose and fatty acid metabolism and hepatic glucose production in a mouse model with hemochromatosis and deleted HFE gene. The authors found that glucose oxidation was decreased and the ratio of fatty acid to glucose oxidation increase.
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Hudson, J. R. Ocular Findings in Haemochromatosis. Br J Ophthalmol 1953, 37 (4), 242.
https://bjo.bmj.com/content/37/4/242.long
This paper describes the effects of hemochromatosis on ocular appearances in five cases. The effects are seen in conjunctiva, iris, lens, and retina.
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Jensen, P. Hemochromatosis: A Disease Often Silent but Not Invisible. American Journal of Roentgenology 1976, 126 (2), 343–351.
https://www.ajronline.org/doi/abs/10.2214/ajr.126.2.343
This article lists characteristics of hemochromatosis that may not be obvious or initially present in a person.
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Johnson, M. B.; Enns, C. A. Diferric Transferrin Regulates Transferrin Receptor 2 Protein Stability. Blood 2004, 104 (13), 4287–4293.
https://ashpublications.org/blood/article/104/13/4287/19004/Diferric-transferrin-regulates-transferrin
This paper highlights the binding of TF and TFR2.
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Kawabata, H. The Mechanisms of Systemic Iron Homeostasis and Etiology, Diagnosis, and Treatment of Hereditary Hemochromatosis. International Journal of Hematology 2018, 107 (1), 31–43.
https://link.springer.com/article/10.1007%2Fs12185-017-2365-3
This article touches upon all four types of hereditary hemochromatosis. The authors specifically studied the mutations of SLC40A1 that encodes for ferroportin, which causes type 4 hemochromatosis.
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Kowdley, K. V. Iron Overload in Patients With Chronic Liver Disease. Gastroenterol Hepatol (N Y) 2016, 12 (11), 695–698.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193089/
This article provides information on the general effects of iron overload on the body.
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Kowdley, K. V.; Brown, K. E.; Ahn, J.; Sundaram, V. ACG Clinical Guideline: Hereditary Hemochromatosis. American Journal of Gastroenterology 2019, 114 (8), 1202–1218.
https://journals.lww.com/ajg/Fulltext/2019/08000/ACG_Clinical_Guideline__Hereditary_Hemochromatosis.11.aspx
This article provides an overview of the types of hereditary hemochromatosis along with ways to diagnose the disease.
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Lebrón, J. A.; Bennett, M. J.; Vaughn, D. E.; Chirino, A. J.; Snow, P. M.; Mintier, G. A.; Feder, J. N.; Bjorkman, P. J. Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor. Cell 1998, 93 (1), 111–123.
https://www.sciencedirect.com/science/article/pii/S0092867400811514
This paper produced the first X-ray crystal structure of the human HFE protein and characterized its interaction with TfR and Tf.
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Mallory, F.B.; Parker, F.; Nye, R.N. Experimental Pigment Cirrhosis due to Copper and its Relation to Hemochromatosis. J Med Res. 1921, 42 (5), 461–490.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2104459/
Hemochromatosis was experimentally produced in animals in order to compare to and better understand the lesions that occur in humans. In order to study the lesion and whereabouts of the pigmentation, the liver was observed due to its active and regenerative capabilities.
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Muckenthaler, M. U. How Mutant HFE Causes Hereditary Hemochromatosis. Blood 2014, 124 (8), 1212–1213.
https://ashpublications.org/blood/article/124/8/1212/33507/How-mutant-HFE-causes-hereditary-hemochromatosis
This paper describes how hepcidin production is affected by the mutant HFE protein.
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Murphree, C. R.; Nguyen, N. N.; Raghunathan, V.; Olson, S. R.; DeLoughery, T.; Shatzel, J. J. Diagnosis and Management of Hereditary Haemochromatosis. Vox Sanguinis. 2020.
https://onlinelibrary.wiley.com/doi/full/10.1111/vox.12896
This review reiterates that hereditary hemochromatosis is due to inherited mutations of the HFE gene, which regulates gastrointestinal iron absorption by hepcidin. The authors summarize existing data and management on the disease and present an algorithm for its diagnosis and management.
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Nemeth, E.; Tuttle, M. S.; Powelson, J.; Vaughn, M. B.; Donovan, A.; Ward, D. M.; Ganz, T.; Kaplan, J. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science 2004, 306 (5704), 2090–2093.
https://science.sciencemag.org/content/306/5704/2090.long
This paper demonstrates that hepcidin interacts with ferroportin, a mechanism of homeostatic iron regulation.
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Nemeth, E.; Ganz, T. The Role of Hepcidin in Iron Metabolism. AHA 2009, 122 (2–3), 78–86.
https://www.karger.com/Article/FullText/243791
This paper gives a detailed explanation on the hepcidin. Hepcidin synthesis, iron-regulatory activity, mechanism of action, and more are explained.
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Nielsen; Carpinteiro; Fischer; Cabeda; Porto; Gabbe. Prevalence of the C282Y and H63D Mutations in the HFE Gene in Patients with Hereditary Haemochromatosis and in Control Subjects from Northern Germany. British Journal of Haematology 1998, 103 (3), 842–845.
https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2141.1998.01037.x?sid=nlm%3Apubmed
This paper determined the two mutations for type I hereditary hemochromatosis. The HFE mutations of C282Y and H63D were found in unrelated patients already diagnosed with hereditary hemochromatosis.
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Olynyk, J. K.; Cullen, D. J.; Aquilia, S.; Rossi, E.; Summerville, L.; Powell, L. W. A Population- Based Study of the Clinical Expression of the Hemochromatosis Gene. New England Journal of Medicine 1999, 341 (10), 718–724.
https://www.nejm.org/doi/full/10.1056/NEJM199909023411002
This paper identified the prevalence of the C282Y and H63D mutations of the HFE gene in Australia. The authors determined that white adults of northern European ancestry were largely homozygous for the C282Y mutation.
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Pantopoulos, K. Function of the Hemochromatosis Protein HFE: Lessons from Animal Models. World J Gastroenterol 2008, 14 (45), 6893–6901.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773850/
This paper provides detailed information on iron regulation and the function hepcidin plays in it and how the HFE protein normally functions in this system.
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Papanikolaou, G.; Samuels, M. E.; Ludwig, E. H.; MacDonald, M. L. E.; Franchini, P. L.; Dubé, M.-P.; Andres, L.; MacFarlane, J.; Sakellaropoulos, N.; Politou, M.; et al. Mutations in HFE2 Cause Iron Overload in Chromosome 1q–Linked Juvenile Hemochromatosis. Nat Genet 2004, 36 (1), 77–82.
https://www.nature.com/articles/ng1274
This study reports the position of chromosome 1q, which is known to be affected in juvenile hemochromatosis. The authors also identified mutations in a previously unknown transcription factor, HFE2.
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Parkkila, S.; Parkkila, A. K.; Waheed, A.; Britton, R. S.; Zhou, X. Y.; Fleming, R. E.; Tomatsu, S.; Bacon, B. R.; Sly, W. S. Cell Surface Expression of HFE Protein in Epithelial Cells, Macrophages, and Monocytes. Haematologica 2000, 85 (4), 340–345.
http://www.haematologica.org/content/85/4/340.long
This article discusses the way the HFE protein is normally expressed on the cell surface. Disruption of the protein hinders cell surface expression.
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Pietrangelo, A. Hereditary Hemochromatosis — A New Look at an Old Disease. New England Journal of Medicine 2004, 350 (23), 2383–2397.
https://www.nejm.org/doi/full/10.1056/NEJMra031573?casa_token=LQn2r7K7W1IAAAAA:AbCJ1M-gTXfj9itPFNWOVla4JS_kYuXxezAOeRkpAzm3MtL4DHFc_1F4wTneOoBKsu5w02yokkB6nyI
This article recounts everything that is known about hereditary hemochromatosis from 1935 until the time it was written in 2004. The author reviews important features of classic HFE-related hereditary hemochromatosis, along with features that are shared by other forms of the disease.
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Pigeon, C.; Ilyin, G.; Courselaud, B.; Leroyer, P.; Turlin, B.; Brissot, P.; Loréal, O. A New Mouse Liver-Specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload. J. Biol. Chem. 2001, 276 (11), 7811–7819.
https://pubmed.ncbi.nlm.nih.gov/11113132/
This paper discusses the role of hepcidin in iron overload.
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Porto, G.; Brissot, P.; Swinkels, D. W.; Zoller, H.; Kamarainen, O.; Patton, S.; Alonso, I.; Morris, M.; Keeney, S. EMQN Best Practice Guidelines for the Molecular Genetic Diagnosis of Hereditary Hemochromatosis (HH). European Journal of Human Genetics 2016, 24 (4), 479–495.
https://www.nature.com/articles/ejhg2015128#citeas
This article states that p.C282Y is not enough to diagnose hereditary hemochromatosis because p.C282Y homozygosity is not of significant indication of a certain diagnosis. The authors present a guideline for the molecular genetic diagnosis of hereditary hemochromatosis.
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Powell, L. W.; Subramaniam, V. N.; Yapp, T. R. Haemochromatosis in the New Millenium. Journal of Hepatology 2000, 32, 48–62.
journal-of-hepatology.eu/article/S0168-8278(00)80415-8/pdf
This article discusses clinical expression of hemochromatosis in patients with the C282Y mutation.
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Reuben, A.; Chung, J. W.; Lapointe, R.; Santos, M. M. The Hemochromatosis Protein HFE 20 Years Later: An Emerging Role in Antigen Presentation and in the Immune System. Immun Inflamm Dis 2017, 5 (3), 218–232.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569368/
This paper provides evidence for the role of HFE in the immune response, which can be used for better treatment and management of hereditary hemochromatosis.
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Rochette, J.; Pointon, J. J.; Fisher, C. A.; Perera, G.; Arambepola, M.; Arichchi, D. S.; De Silva, S.; Vandwalle, J. L.; Monti, J. P.; Old, J. M.; Merryweather-Clarke, A. T.; Weatherall, D. J.; Robson, K. J. Multicentric Origin of Hemochromatosis Gene (HFE) Mutations. Am. J. Hum. Genet. 1999, 64 (4), 1056–1062.
https://pubmed.ncbi.nlm.nih.gov/10090890/
This article provides information on the presence of the C282Y and H63D mutations of hereditary hemochromatosis in different ethnic groups.
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Rous, P.; Oliver, J. EXPERIMENTAL HEMOCHROMATOSIS. J Exp Med 1918, 28 (5), 629–644.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2126298/
This paper identified and verified characteristics present in hemochromatosis that allow for its diagnosis, specifically pigmentation and cirrhosis. These claims were made by comparing rabbit models to human cases, in organs such as the spleen, liver, pancreas, kidneys, and skin.
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Roy, C. N.; Andrews, N. C. Recent Advances in Disorders of Iron Metabolism: Mutations, Mechanisms and Modifiers. Hum Mol Genet 2001, 10 (20), 2181–2186.
https://academic.oup.com/hmg/article/10/20/2181/559340
The authors of this study worked to identify more genes that are involved in non-HFE-associated iron overload. By understanding iron transport, they have identified mutations in Fpn1/Ireg1/MTP1, Sfxn1, and Dcytb.
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Ruchala, P.; Nemeth, E. The Pathophysiology and Pharmacology of Hepcidin. Trends in Pharmacological Sciences 2014, 35 (3), 155–161.
https://www.sciencedirect.com/science/article/abs/pii/S0165614714000133
This paper provides possible treatments for hemochromatosis that target hepcidin expression.
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Sankaran, V. G.; Weiss, M. J. Anemia: Progress in Molecular Mechanisms and Therapies. Nature Medicine 2015, 21 (3), 221–230.
https://www.nature.com/articles/nm.3814
This article provides information on the normal function of hepcidin and how it is impacted by hereditary hemochromatosis.
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Santos, M.; Schilham, M. W.; Rademakers, L. H.; Marx, J. J.; de Sousa, M.; Clevers, H. Defective Iron Homeostasis in Beta 2-Microglobulin Knockout Mice Recapitulates Hereditary Hemochromatosis in Man. J. Exp. Med. 1996, 184 (5), 1975–1985.
https://pubmed.ncbi.nlm.nih.gov/8920884/
This paper provides information on the effects of B2-microglobulin knockout seen in patients. Without its association to B2-microglobulin, the HFE protein structure malfunctions.
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Schmidt, P. J.; Toran, P. T.; Giannetti, A. M.; Bjorkman, P. J.; Andrews, N. C. The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression. Cell Metabolism 2008, 7 (3), 205–214.
https://www.sciencedirect.com/science/article/pii/S1550413107003737
This paper describes how hepcidin expression occurs when HFE protein and TFR1 are not complexed.
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Simon, M.; Bourel, M.; Fauchet, R.; Genetet, B. Association of HLA-A3 and HLA-B14 Antigens with Idiopathic Haemochromatosis. Gut 1976, 17 (5), 332–334.
https://gut.bmj.com/content/17/5/332.long
The gene that is responsible for hereditary hemochromatosis was determined because of the close linkage to MHC.
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Simon, M.; Bourel, M.; Genetet, B.; Fauchet, R. Idiopathic Hemochromatosis. New England Journal of Medicine 1977, 297 (19), 1017–1021.
https://www.nejm.org/doi/full/10.1056/NEJM197711102971901?casa_token=Eh3d1hNvJq4AAAAA:g5cgzshzr6CZyQbgLKkkZZ48hck6gfVW4xLe1ticZWQOX53Xk88a7_pzzHnH6hT5R30j1WPXx_VB5Sc
This study supports that hemochromatosis is closely linked to the HLA-A locus, which is one of the three major types of human MHC class I cell surface receptors. The authors claim that this relationship could help in early detection of hemochromatosis before iron overload.
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Ulvik, R. J. Hereditary Haemochromatosis through 150 Years. Tidsskrift for Den norske legeforening 2016.
https://tidsskriftet.no/en/2016/12/medical-history/hereditary-haemochromatosis-through-150-years
This website provides a timeline of all of the important discoveries of hemochromatosis over the last 150 years, from its first identification to its present-day characteristics.
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Waheed, A.; Parkkila, S.; Saarnio, J.; Fleming, R. E.; Zhou, X. Y.; Tomatsu, S.; Britton, R. S.; Bacon, B. R.; Sly, W. S. Association of HFE Protein with Transferrin Receptor in Crypt Enterocytes of Human Duodenum. Proc Natl Acad Sci U S A 1999, 96 (4), 1579–1584.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15523/
This article highlights the HFE protein mechanism in enterocytes of the duodenum.
a
Watt, R. K. The Many Faces of the Octahedral Ferritin Protein. Biometals 2011, 24 (3), 489–500.
https://pubmed.ncbi.nlm.nih.gov/21267633/?dopt=Abstract
This article explains the characteristics of the ferritin protein.
a
Wessling-Resnick, M. Excess Iron: Considerations Related to Development and Early Growth. Am. J. Clin. Nutr. 2017, 106 (Suppl 6), 1600S-1605S.
https://pubmed.ncbi.nlm.nih.gov/29070548/
This article elaborates on the issue of excess iron that arise in the body.
a
Willis, G.; Wimperis, J. Z.; Lonsdale, R.; Fellows, I. W.; Watson, M. A.; Skipper, L. M.; Jennings, B. A. Incidence of Liver Disease in People with HFE Mutations. Gut 2000, 46 (3), 401–404.
https://www.ncbi.nlm.nih.gov/pubmed/10673304
A group of people who were not receiving treatment for hemochromatosis were observed and biopsied for the development of cirrhosis and liver cancer.
a
Wortsman, J. Hemochromatosis. New England Journal of Medicine 1996, 335 (24).
https://www.nejm.org/doi/10.1056/NEJM199612123352406
Magnetic resonance images show the effects of hemochromatosis on the liver of a 62-year-old woman. Two panels of results are provided, before and after being treated with phlebotomy in order to treat the effects.
a
Wu, X.; Wang, Y.; Wu, Q.; Cheng, W.-H.; Liu, W.; Zhao, Y.; Mayeur, C.; Schmidt, P. J.; Yu, P. B.; Wang, F.; Xia, Y. HFE Interacts with the BMP Type I Receptor ALK3 to Regulate Hepcidin Expression. Blood 2014, 124 (8), 1335–1343.
https://ashpublications.org/blood/article/124/8/1335/33558/HFE-interacts-with-the-BMP-type-I-receptor-ALK3-to
This paper provides more insight into the way hepcidin expression is affected by HFE protein. The authors conclude that HFE induces hepcidin expression through the BMP pathway in which HFE interacts with ALK3 to stabilize the ALK3 protein and increase ALK3 expression.
a
Zhou, X. Y.; Tomatsu, S.; Fleming, R. E.; Parkkila, S.; Waheed, A.; Jiang, J.; Fei, Y.; Brunt, E. M.; Ruddy, D. A.; Prass, C. E.; Schatzman, R. C.; O’Neill, R.; Britton, R. S.; Bacon, B. R.; Sly, W. S. HFE Gene Knockout Produces Mouse Model of Hereditary Hemochromatosis. PNAS 1998, 95 (5), 2492–2497.
https://www.pnas.org/content/95/5/2492.long
This article verified that mutations in the HFE gene result in iron overload.
a
Zoller, H.; Henninger, B. Pathogenesis, Diagnosis and Treatment of Hemochromatosis. DDI 2016, 34 (4), 364–373.
https://www.karger.com/Article/Abstract/444549
This paper provides insight into possible treatments for hemochromatosis.
Normal Function of Key Players
