Genetic mechanisms and modifying factors in hereditary hemochromatosis

Nature Reviews Gastroenterology and Hepatology

Volumn 7, Issue 1, 2010, Pages 50-58

  Weiss, Günter ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL; ASCORBIC ACID; BETA 2 MICROGLOBULIN; BONE MORPHOGENETIC PROTEIN 6; CARRIER PROTEIN; COPPER; GENE PRODUCT; HEMOJUVELIN; HEPCIDIN; HFE PROTEIN; HYPOXIA INDUCIBLE FACTOR 2ALPHA; IRON; NIFEDIPINE; OMEPRAZOLE; PROTEIN CYBRD1; PROTEIN SLC40A1; SMAD PROTEIN; TRANSFERRIN; UNCLASSIFIED DRUG;

AGE; ALCOHOL CONSUMPTION; AMINO ACID SUBSTITUTION; AUTOSOMAL RECESSIVE INHERITANCE; CHRONIC INFLAMMATION; DIET; DRUG USE; ENVIRONMENTAL FACTOR; ERYTHROPOIESIS; FERRITIN BLOOD LEVEL; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE MUTATION; GENETIC POLYMORPHISM; HEMOCHROMATOSIS; HEPATITIS C; HEREDITARY HEMOCHROMATOSIS; HEREDITARY HEMOCHROMATOSIS TYPE 1; HEREDITY; HETEROZYGOTE; HOMOZYGOTE; HUMAN; INFLAMMATION; INTESTINE ABSORPTION; INTESTINE CELL; IRON ABSORPTION; IRON METABOLISM; IRON OVERLOAD; IRON TRANSPORT; MACROPHAGE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PENETRANCE; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

GENETIC PREDISPOSITION TO DISEASE; GENETIC TESTING; HEMOCHROMATOSIS; HUMANS; RISK FACTORS;

EID: 75049084543     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2009.201     Document Type: Review

References (120)

1. Olynyk, J. K., Trinder, D., ramm, G. A., Britton, R. S. & Bacon, B. R. Hereditary hemochromatosis in the post-HFe era. Hepatology 48, 991-1001 (2008).
2. Pietrangelo, A. Hereditary hemochromatosis- a new look at an old disease. N. Engl. J. Med. 350, 2383-2397 (2004).
3. Adams, P. C. & Barton, J. C. Haemochromatosis. Lancet 370, 1855-1860 (2007).
4. Anderson, G. J. & Powell, L. W. HFe and non- HFe hemochromatosis. Int. J. Hematol. 76, 203-207 (2002).
5. Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399-408 (1996).
6. Brissot, P. et al. Current approach to hemochromatosis. Blood Rev. 22, 195-210 (2008).
7. Kowdley, K. v. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127 (Suppl. 1), S79-S86 (2004).
8. Bacon, B. R. & Britton, R. S. Clinical penetrance of hereditary hemochromatosis. N. Engl. J. Med. 358, 291-292 (2008).
9. Hentze, M. W., Muckenthaler, M. U. & Andrews, N. C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117, 285-297 (2004).
10. Knutson, M. D., vafa, M. r., Haile, D. J. & Wessling-resnick, M. Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 102, 4191-4197 (2003).
11. Delaby, C., Pilard, N., Puy, H. & Canonne- Hergaux, F. Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mrNA induction by haem, followed by iron-dependent protein expression. Biochem. J. 411, 123-131 (2008).
12. Frazer, D. M. & Anderson, G. J. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol. Dis. 30, 288-297 (2003).
13. Cook, J. D., Dassenko, S. A. & Lynch, S. R. Assessment of the role of nonheme-iron availability in iron balance. Am. J. Clin. NutR. 54, 717-722 (1991).
14. Shayeghi, M. et al. Identification of an intestinal heme transporteR. Cell 122, 789-801 (2005).
15. Qiu, A. et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928 (2006).
16. Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporteR. Nature 388, 482-488 (1997).
17. Zoller, H. et al. expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 120, 1412-1419 (2001).
18. Donovan, A. et al. The iron exporter ferroportin/ Slc40a1 is essential for iron homeostasis. Cell. Metab. 1, 191-200 (2005).
19. Ludwiczek, S., Theurl, I., Bahram, S., Schumann, K. & Weiss, G. regulatory networks for the control of body iron homeostasis and their dysregulation in HFe mediated hemochromatosis. J. Cell. Physiol. 204, 489-499 (2005).
20. Valore, E. V. & Ganz, T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol. Dis. 40, 132-138 (2008).
21. Park, C. H., Valore, E. V., Waring, A. J. & Ganz, T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806-7810 (2001).
22. Pigeon, C. et al. A new mouse liver-specific gene, Encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 276, 7811-7819 (2001).
23. Nicolas, G. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037-1044 (2002).
24. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093 (2004).
25. Papanikolaou, G. et al. Mutations in HFe2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77-82 (2004).
26. Niederkofler, V., Salie, R. & Arber, S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J. Clin. Invest. 115, 2180-2186 (2005).
27. Huang, F. W., Pinkus, J. L., Pinkus, G. S., Fleming, M. D. & Andrews, N. C. A mouse model of juvenile hemochromatosis. J. Clin. Invest. 115, 2187-2191 (2005).
28. Babitt, J. L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539 (2006).
29. Truksa, J., Peng, H., Lee, P. & Beutler, E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. BR. J. Haematol. 139, 138-147 (2007).
30. Lin, L. et al. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 110, 2182-2189 (2007).
31. Andriopoulos, B. Jr et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487 (2009).
32. Meynard, D. et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481 (2009).
33. Xia, Y., Babitt, J. L., Sidis, Y., Chung, R. T. & Lin, H. Y. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111, 5195-5204 (2008).
34. Kautz, L. et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112, 1503-1509 (2008).
35. Arndt, S. et al. Iron-induced expression of BMP6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo. Gastroenterology doi:10.1053/ j.gastro.2009.09.048
36. Babitt, J. L. et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939 (2007).
37. Wang, R. H. et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell. Metab. 2, 399-409 (2005).
38. Zhang, A. S., Yang, F., Wang, J., Tsukamoto, H. & enns, C. A. Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4- induced hepcidin expression. J. Biol. Chem. 284, 22580-22589 (2009).
39. Pagani, A., Silvestri, L., Nai, A. & Camaschella, C. Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response. Haematologica 93, 1466-1472 (2008).
40. roetto, A. et al. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70r). Blood 103, 2407-2409 (2004).
41. Island, M. L. et al. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFe related hemochromatosis. Haematologica 94, 720-724 (2009).
42. Casanovas, G., Mleczko-Sanecka, K., Altamura, S., Hentze, M. W. & Muckenthaler, M. U. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJv/BMP/SMAD. J. Mol. Med. 87, 471-480 (2009).
43. Bennett, M. J., Lebron, J. A. & Bjorkman, P. J. Crystal structure of the hereditary haemochromatosis protein HFe complexed with transferrin receptoR. Nature 403, 46-53 (2000).
44. Walsh, A. et al. The clinical relevance of compound heterozygosity for the C282Y and H263D substitutions in hemochromatosis. Clin. Gastroenterol. Hepatol. 4, 1403-1410 (2006).
45. Moirand, R. et al. HFe based re-evaluation of heterozygous hemochromatosis. Am. J. Med. Genet. 111, 356-361 (2002).
46. Gurrin, L. C. et al. HFe C282Y/H263D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology 50, 94-101 (2009).
47. Chua, A. C. et al. The role of Hfe in transferrinbound iron uptake by hepatocytes. Hepatology 47, 1737-1744 (2008).
48. vujic Spasic, M. et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell. Metab. 7, 173-178 (2008).
49. 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. Metab. 7, 205-214 (2008).
50. Gao, J. et al. Interaction of the hereditary hemochromatosis protein HFe with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell. Metab. 9, 217-227 (2009).
51. Nemeth, E., roetto, A., Garozzo, G., Ganz, T. & Camaschella, C. Hepcidin is decreased in TFr2 hemochromatosis. Blood 105, 1803-1806 (2005).
52. Fleming, R. E. et al. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc. Natl Acad. Sci. USA 99, 10653-10658 (2002).
53. Kautz, L. et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 144, 2515-2520 (2009).
54. Corradini, E. et al. Bone morphogenetic protein signaling is impaired in a HFe knockout mouse model of hemochromatosis. Gastroenterology 137, 1489-1497 (2009).
55. ramey, G., Deschemin, J. C. & vaulont, S. Crosstalk between the mitogen activated protein kinase and bone morphogenetic protein/ hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 94, 765-772 (2009).
56. Wallace, D. F. et al. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology doi:10.1002/hep.23198
57. Pietrangelo, A. et al. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128, 470-479 (2005).
58. Lee, P. L. & Beutler, E. regulation of hepcidin and iron-overload disease. Annu. Rev. Pathol. 4, 489-515 (2009).
59. Drakesmith, H. et al. resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 106, 1092-1097 (2005). (Pubitemid 41076459)
60. Montosi, G. et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108, 619-623 (2001).
61. Gordeuk, V. R. et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1). Blood Cells Mol. Dis. 31, 299-304 (2003).
62. Njajou, O. T. et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat. Genet. 28, 213-214 (2001).
63. Lok, C. Y. et al. Iron overload in the Asian community. Blood 114, 20-25 (2009).
64. Adams, P. C. et al. Hemochromatosis and ironoverload screening in a racially diverse population. N. Engl. J. Med. 352, 1769-1778 (2005).
65. Arden, K. E. et al. A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 52, 1215-1217 (2003).
66. Wallace, D. F. et al. A novel mutation in ferroportin implicated in iron overload. J. Hepatol. 46, 921-926 (2007).
67. Weinberg, E. D. Survival advantage of the hemochromatosis C282Y mutation. Perspect. Biol. Med. 51, 98-102 (2008).
68. Cairo, G. et al. Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis. Blood 89, 2546-2553 (1997).
69. Oexle, H. et al. Pathways for the regulation of interferon-gamma- inducible genes by iron in human monocytic cells. J. Leukoc. Biol. 74, 287-294 (2003).
70. Nairz, M. et al. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2. Blood 114, 3642-3651 (2009).
71. Olakanmi, O., Schlesinger, L. S. & Britigan, B. E. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J. Leukoc. Biol. 81, 195-204 (2007).
72. Pedersen, P. & Milman, N. Genetic screening for HFe hemochromatosis in 6,020 Danish men: penetrance of C282Y, H263D, and S65C variants. Ann. Hematol. 88, 775-784 (2009).
73. Gurrin, L. C. et al. The natural history of serum iron indices for HFe C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology 135, 1945-1952 (2008).
74. Ajioka, R. S. & Kushner, J. P. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood 101, 3351-3353 (2003).
75. Andersen, R. V., Tybjaerg-Hansen, A., Appleyard, M., Birgens, H. & Nordestgaard, B. G. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 103, 2914-2919 (2004).
76. Allen, K. J. et al. Iron-overload-related disease in HFe hereditary hemochromatosis. N. Engl. J. Med. 358, 221-230 (2008).
77. Wood, M. J., Powell, L. W. & ramm, G. A. environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 111, 4456-4462 (2008).
78. Dupic, F. et al. Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mrNAs between mouse strains. Gastroenterology 122, 745-751 (2002).
79. Levy, J. E., Montross, L. K. & Andrews, N. C. Genes that modify the hemochromatosis phenotype in mice. J. Clin. Invest. 105, 1209-1216 (2000).
80. Ludwiczek, S., Theurl, I., Artner-Dworzak, E., Chorney, M. & Weiss, G. Duodenal HFe expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability. J. Mol. Med. 82, 373-382 (2004).
81. Altes, A. et al. Mutations in HAMP and HJv genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFe gene. Ann. Hematol. 88, 951-955 (2009).
82. Milet, J. et al. Common variants in the BMP2, BMP4, and HJv genes of the hepcidin regulation pathway modulate HFe hemochromatosis penetrance. Am. J. Hum. Genet. 81, 799-807 (2007).
83. rivers, C. A. et al. Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HeIrS) Study. Blood Cells Mol. Dis. 38, 247-252 (2007).
84. Tanno, T. et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 13, 1096-1101 (2007).
85. Du, X. et al. The serine protease TMPrSS6 is required to sense iron deficiency. Science 320, 1088-1092 (2008).
86. Silvestri, L. et al. The serine protease matriptase-2 (TMPrSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell. Metab. 8, 502-511 (2008).
87. Tanno, T. et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114, 181-186 (2009).
88. Huang, H., Constante, M., Layoun, A. & Santos, M. M. Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood 113, 3593-3599 (2009).
89. Constantine, C. C. et al. SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis. BMC Med. Genet. 9, 18 (2008).
90. Kim, B. E., Nevitt, T. & Thiele, D. J. Mechanisms for copper acquisition, distribution and regulation. Nat. Chem. Biol. 4, 176-185 (2008).
91. Gouya, L. et al. Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFe-hemochromatosis modifier gene. Gastroenterology 132, 679-686 (2007).
92. Tolosano, E. et al. Haptoglobin modifies the hemochromatosis phenotype in mice. Blood 105, 3353-3355 (2005).
93. Constantine, C. C. et al. A novel association between a SNP in CYBrD1 and serum ferritin levels in a cohort study of HFe hereditary haemochromatosis. BR. J. Haematol. 147, 140-149 (2009).
94. Shah, Y. M., Matsubara, T., Ito, S., Yim, S. H. & Gonzalez, F. J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell. Metab. 9, 152-164 (2009).
95. Mastrogiannaki, M. et al. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest. 119, 1159-1166 (2009).
96. Harrison-Findik, D. D. et al. Alcohol metabolismmediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J. Biol. Chem. 281, 22974-22982 (2006).
97. Duane, P., raja, K. B., Simpson, R. J. & Peters, T. J. Intestinal iron absorption in chronic alcoholics. Alcohol Alcohol. 27, 539-544 (1992).
98. Kohgo, Y., Ikuta, K., Ohtake, T., Torimoto, Y. & Kato, J. Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance. World J. Gastroenterol. 13, 4699-4706 (2007).
99. Flanagan, J. M., Peng, H. & Beutler, E. effects of alcohol consumption on iron metabolism in mice with hemochromatosis mutations. Alcohol Clin. Exp. Res. 31, 138-143 (2007).
100. Wallace, D. F. & Subramaniam, V. N. Co-factors in liver disease: The role of HFe-related hereditary hemochromatosis and iron. Biochim. Biophys. Acta 1790, 663-670 (2009).
101. Fargion, S. et al. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 2448-2455 (2001).
102. Younossi, Z. M. et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 30, 847-850 (1999).
103. Aigner, E. et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am. J. Clin. NutR. 87, 1374-1383 (2008).
104. Jacobs, E. M. et al. Severity of iron overload of proband determines serum ferritin levels in families with HFe-related hemochromatosis: the Hemochromatosis FAmily Study. J. Hepatol. 50, 174-183 (2009).
105. Powell, E. E. et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 129, 1937-1943 (2005).
106. Piperno, A. et al. Blunted hepcidin response to oral iron challenge in HFe-related hemochromatosis. Blood 110, 4096-4100 (2007).
107. Milward, E. A. et al. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFe gene mutations. Mayo Clin. Proc. 83, 543-549 (2008).
108. Aigner, E. et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology 135, 680-688 (2008).
109. Golubov, J., Flanagan, P. & Adams, P. Inhibition of iron absorption by omeprazole in rat model. Dig. Dis. Sci. 36, 405-408 (1991).
110. Hutchinson, C., Geissler, C. A., Powell, J. J. & Bomford, A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 56, 1291-1295 (2007).
111. Ludwiczek, S. et al. Ca(2+) channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat. Med. 13, 448-454 (2007).
112. Nishina, S. et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134, 226-238 (2008).
113. Tung, B. Y. et al. Hepatitis C, iron status, and disease severity: relationship with HFe mutations. Gastroenterology 124, 318-326 (2003).
114. Gehrke, S. G. et al. Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCv genotype. J. Mol. Med. 81, 780-787 (2003).
115. Kazemi-Shirazi, L. et al. The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. Gastroenterology 116, 127-134 (1999).
116. Theurl, I. et al. regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and Therapeutic implications. Blood 113, 5277-5286 (2009).
117. Pantopoulos, K. & Hentze, M. W. rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 14, 2917-2924 (1995).
118. Cheng, R. et al. Differences in hepatic phenotype between hemochromatosis patients with HFe C282Y homozygosity and oTher HFe genotypes. J. Clin. Gastroenterol. 43, 569-573 (2009).
119. Mair, S. M. & Weiss, G. New pharmacological concepts for the treatment of iron overload disorders. Curr. Med. Chem. 16, 576-590 (2009).
120. Yu, P. B. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4, 33-41 (2008).