Identification of Genes for Hereditary Hemochromatosis

  • Glenn S. GerhardEmail author
  • Barbara V. Paynton
  • Johanna K. DiStefano
Part of the Methods in Molecular Biology book series (MIMB, volume 1706)


Hereditary hemochromatosis (HH) is one of the most common genetically transmitted conditions in individuals of Northern European ancestry. The disease is characterized by excessive intestinal absorption of dietary iron, resulting in pathologically high iron storage in tissues and organs. If left untreated, HH can damage joints and organs, and eventually lead to death. There are four main classes of HH, as well as five individual molecular subtypes, caused by mutations in five genes, and the approaches implemented in the discovery of each HH type have specific histories and unique aspects. In this chapter, we review the genetics of the different HH types, including the strategies used to detect the causal variants in each case and the manner in which genetic variants were found to affect iron metabolism.

Key words

Hemochromatosis Linkage mapping Iron absorption Iron overload HFE Hemojuvelin (HJV) Hepcidin (HAMP) Transferrin receptor 2 (TFR2) Ferroportin 1 (SLC40A1) 


  1. 1.
    Gulec S, Anderson GJ, Collins JF (2014) Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 307(4):G397–G409CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hoppe M, Brun B, Larsson MP, Moraeus L, Hulthen L (2013) Heme iron-based dietary intervention for improvement of iron status in young women. Nutrition 29(1):89–95CrossRefPubMedGoogle Scholar
  3. 3.
    Silva B, Faustino P (2015) An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 1852(7):1347–1359CrossRefPubMedGoogle Scholar
  4. 4.
    West AR, Oates PS (2008) Mechanisms of heme iron absorption: current questions and controversies. World J Gastroenterol 14(26):4101–4110CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hooda J, Shah A, Zhang L (2014) Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients 6(3):1080–1102CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fleming MD, Hamza I (2012) Mitochondrial heme: an exit strategy at last. J Clin Invest 122(12):4328–4330CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bailey RL, West KP Jr, Black RE (2015) The epidemiology of global micronutrient deficiencies. Ann Nutr Metab 66(Suppl 2):22–33CrossRefPubMedGoogle Scholar
  8. 8.
    Miller JL (2013) Iron deficiency anemia: a common and curable disease. Cold Spring Harb Perspect Med 3(7):a011866CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    McDonagh MS, Blazina I, Dana T, Cantor A, Bougatsos C (2015) Screening and routine supplementation for iron deficiency anemia: a systematic review. Pediatrics 135(4):723–733CrossRefPubMedGoogle Scholar
  10. 10.
    Uzel C, Conrad ME (1998) Absorption of heme iron. Semin Hematol 35(1):27–34PubMedGoogle Scholar
  11. 11.
    Hunt JR, Roughead ZK (2000) Adaptation of iron absorption in men consuming diets with high or low iron bioavailability. Am J Clin Nutr 71(1):94–102PubMedGoogle Scholar
  12. 12.
    Conrad ME, Umbreit JN (2000) Iron absorption and transport-an update. Am J Hematol 64(4):287–298CrossRefPubMedGoogle Scholar
  13. 13.
    Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M (2004) The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 115(4):269–279CrossRefPubMedGoogle Scholar
  14. 14.
    Felitti VJ, Beutler E (1999) New developments in hereditary hemochromatosis. Am J Med Sci 318(4):257–268CrossRefPubMedGoogle Scholar
  15. 15.
    Trousseau A (1865) Glycosurie, diabète sucre. In: Clinique médicale de l’Hôtel-Dieu de Paris, vol 2. J.-B. Balliere, Paris, pp 663–698Google Scholar
  16. 16.
    Troisier M (1871) Diabète sucre. Bull Soc Anat (Paris) 44:231–235Google Scholar
  17. 17.
    von Recklinghausen FD (1889) Ueber Hamochromatose. Bericht der Naturforscher-Versammlung zu Heidelberg. p 324Google Scholar
  18. 18.
    Sheldon JH (1935) Haemochromatosis. Oxford University Press, H. Milford, Oxford, p 382Google Scholar
  19. 19.
    McKusick VA (1998) Mendelian inheritance in man: a catalog of human genes and genetic disorders, vol 1. Johns Hopkins University Press, Baltimore, MDGoogle Scholar
  20. 20.
    Simon M, Le Mignon L, Fauchet R, Yaouanq J, David V, Edan G, Bourel M (1987) A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 41(2):89–105PubMedPubMedCentralGoogle Scholar
  21. 21.
    Cassidy LM, Martiniano R, Murphy EM, Teasdale MD, Mallory J, Hartwell B, Bradley DG (2016) Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome. Proc Natl Acad Sci U S A 113(2):368–373CrossRefPubMedGoogle Scholar
  22. 22.
    Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ (1997) Global prevalence of putative haemochromatosis mutations. J Med Genet 34(4):275–278CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Barton JC, Acton RT, Dawkins FW, Adams PC, Lovato L, Leiendecker-Foster C, McLaren CE, Reboussin DM, Speechley MR, Gordeuk VR, McLaren GD, Sholinsky P, Harris EL (2005) Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study. Genet Test 9(3):231–241CrossRefPubMedGoogle Scholar
  24. 24.
    Barton JC, Edwards CQ, Acton RT (2015) HFE gene: structure, function, mutations, and associated iron abnormalities. Gene 574(2):179–192CrossRefPubMedGoogle Scholar
  25. 25.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13(4):399–408CrossRefPubMedGoogle Scholar
  26. 26.
    Lovett M, Kere J, Hinton LM (1991) Direct selection: a method for the isolation of cDNAs encoded by large genomic regions. Proc Natl Acad Sci U S A 88(21):9628–9632CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Church DM, Stotler CJ, Rutter JL, Murrell JR, Trofatter JA, Buckler AJ (1994) Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nat Genet 6(1):98–105CrossRefPubMedGoogle Scholar
  28. 28.
    Venditti CP, Harris JM, Geraghty DE, Chorney MJ (1994) Mapping and characterization of non-HLA multigene assemblages in the human MHC class I region. Genomics 22(2):257–266CrossRefPubMedGoogle Scholar
  29. 29.
    Wallace DF, Subramaniam VN (2016) The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet Med 18(6):618–626CrossRefPubMedGoogle Scholar
  30. 30.
    Le Gac G, Ferec C (2005) The molecular genetics of haemochromatosis. Eur J Hum Genet 13(11):1172–1185CrossRefPubMedGoogle Scholar
  31. 31.
    Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D’Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C (1999) Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet 64(5):1388–1393CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36(1):77–82CrossRefPubMedGoogle Scholar
  33. 33.
    Lee PL, Beutler E, Rao SV, Barton JC (2004) Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 103(12):4669–4671CrossRefPubMedGoogle Scholar
  34. 34.
    De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C (2002) Natural history of juvenile haemochromatosis. Br J Haematol 117(4):973–979CrossRefPubMedGoogle Scholar
  35. 35.
    Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (2002) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A 99(7):4596–4601CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25(1):14–15CrossRefPubMedGoogle Scholar
  37. 37.
    Camaschella C, Fargion S, Sampietro M, Roetto A, Bosio S, Garozzo G, Arosio C, Piperno A (1999) Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology 29(5):1563–1564CrossRefPubMedGoogle Scholar
  38. 38.
    Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274(30):20826–20832CrossRefPubMedGoogle Scholar
  39. 39.
    Aguilar-Martinez P, Esculie-Coste C, Bismuth M, Giansily-Blaizot M, Larrey D, Schved JF (2001) Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis. Blood Cells Mol Dis 27(1):290–293CrossRefPubMedGoogle Scholar
  40. 40.
    Inheritance of idiopathic haemochromatosis (1977) Lancet 1(8021):1106–1107Google Scholar
  41. 41.
    Pietrangelo A, Montosi G, Totaro A, Garuti C, Conte D, Cassanelli S, Fraquelli M, Sardini C, Vasta F, Gasparini P (1999) Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 341(10):725–732CrossRefPubMedGoogle Scholar
  42. 42.
    Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P (2001) A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28(3):213–214CrossRefPubMedGoogle Scholar
  43. 43.
    Haile DJ (2000) Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization. Cytogenet Cell Genet 88(3-4):328–329CrossRefPubMedGoogle Scholar
  44. 44.
    Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403(6771):776–781CrossRefPubMedGoogle Scholar
  45. 45.
    Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A (2001) Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108(4):619–623CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  • Glenn S. Gerhard
    • 1
    Email author
  • Barbara V. Paynton
    • 2
  • Johanna K. DiStefano
    • 3
  1. 1.Department of Medical Genetics and Molecular Biochemistry, 960 Medical Education and Research Building (MERB)Lewis Katz School of Medicine at Temple UniversityPhiladelphiaUSA
  2. 2.Department of Medical Genetics and Molecular BiologyThe Lewis Katz School of Medicine at Temple UniversityPhiladelphiaUSA
  3. 3.Translational Genomics Research InstitutePhoenixUSA

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