Abstract
Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.
Similar content being viewed by others
References
Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, Bahlo M, Nisselle AE, Vulpe CD, Anderson GJ, Southey MC, Giles GG, English DR, Hopper JL, Olynyk JK, Powell LW, Gertig DM (2008) Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 358:221–230
Bagley DC, Paradkar PN, Kaplan J, Ward DM (2012) Mon1a protein acts in trafficking through the secretory apparatus. J Biol Chem 287:25577–25588
Bensaid M, Fruchon S, Mazeres C, Bahram S, Roth MP, Coppin H (2004) Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology 126:1400–1408
Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, Hottenga JJ, Henders AK, Campbell MJ, Wallace L, Frazer IH, Heath AC, de Geus EJ, Nyholt DR, Visscher PM, Penninx BW, Boomsma DI, Martin NG, Montgomery GW, Whitfield JB (2009a) Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41:1173–1175
Benyamin B, McRae AF, Zhu G, Gordon S, Henders AK, Palotie A, Peltonen L, Martin NG, Montgomery GW, Whitfield JB, Visscher PM (2009b) Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 84:60–65
Cherukuri S, Potla R, Sarkar J, Nurko S, Harris ZL, Fox PL (2005) Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2:309–319
Constantine CC, Anderson GJ, Vulpe CD, McLaren CE, Bahlo M, Yeap HL, Gertig DM, Osborne NJ, Bertalli NA, Beckman KB, Chen V, Matak P, McKie AT, Delatycki MB, Olynyk JK, English DR, Southey MC, Giles GG, Hopper JL, Allen KJ, Gurrin LC (2009) 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
Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F (2005a) Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 106:3979–3984
Delaby C, Pilard N, Hetet G, Driss F, Grandchamp B, Beaumont C, Canonne-Hergaux F (2005b) A physiological model to study iron recycling in macrophages. Exp Cell Res 310:43–53
Demant P, Hart AA (1986) Recombinant congenic strains—a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics 24:416–422
Distante S, Elmberg M, Foss Haug KB, Ovstebo R, Berg JP, Kierulf P, Hultcrantz R, Bell H (2003) Tumour necrosis factor alpha and its promoter polymorphisms’ role in the phenotypic expression of hemochromatosis. Scand J Gastroenterol 38:871–877
Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200
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 13:399–408
Fleming RE, Holden CC, Tomatsu S, Waheed A, Brunt EM, Britton RS, Bacon BR, Roopenian DC, Sly WS (2001) Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc Natl Acad Sci USA 98:2707–2711
Goncalves AS, Muzeau F, Blaybel R, Hetet G, Driss F, Delaby C, Canonne-Hergaux F, Beaumont C (2006) Wild-type and mutant ferroportins do not form oligomers in transfected cells. Biochem J 396:265–275
Gouya L, Muzeau F, Robreau AM, Letteron P, Couchi E, Lyoumi S, Deybach JC, Puy H, Fleming R, Demant P, Beaumont C, Grandchamp B (2007) Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene. Gastroenterology 132:679–686
Grant GR, Robinson SW, Edwards RE, Clothier B, Davies R, Judah DJ, Broman KW, Smith AG (2006) Multiple polymorphic loci determine basal hepatic and splenic iron status in mice. Hepatology 44:174–185
Groot PC, Moen CJ, Dietrich W, Stoye JP, Lander ES, Demant P (1992) The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 6:2826–2835
Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C (2004) HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 103:2835–2840
Kinchen JM, Ravichandran KS (2010) Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature 464:778–782
Krayenbuehl PA, Maly FE, Hersberger M, Wiesli P, Himmelmann A, Eid K, Greminger P, Vetter W, Schulthess G (2006) Tumor necrosis factor-alpha −308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Clin Chem 52:1552–1558
Leboeuf RC, Tolson D, Heinecke JW (1995) Dissociation between tissue iron concentrations and transferrin saturation among inbred mouse strains. J Lab Clin Med 126:128–136
Lehner B (2011) Molecular mechanisms of epistasis within and between genes. Trends Genet 27:323–331
Levy JE, Montross LK, Andrews NC (2000) Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 105:1209–1216
Manly KF, Cudmore RH Jr, Meer JM (2001) Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12:930–932
McLachlan S, Lee SM, Steele TM, Hawthorne PL, Zapala MA, Eskin E, Schork NJ, Anderson GJ, Vulpe CD (2011) In silico QTL mapping of basal liver iron levels in inbred mouse strains. Physiol Genomics 43:136–147
Milet J, Dehais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M, Morcet J, Brissot P, David V, Deugnier Y, Mosser J (2007) 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
Milet J, Le Gac G, Scotet V, Gourlaouen I, Theze C, Mosser J, Bourgain C, Deugnier Y, Ferec C (2010) A common SNP near BMP2 is associated with severity of the iron burden in HFE p. C282Y homozygous patients: a follow-up study. Blood Cells Mol Dis 44:34–37
Mura C, Raguenes O, Ferec C (1999) HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93:2502–2505
Nai A, Pagani A, Silvestri L, Campostrini N, Corbella M, Girelli D, Traglia M, Toniolo D, Camaschella C (2011) TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 118:4459–4462
Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A, Andrews NC, Vaulont S (2003) Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34:97–101
Pelucchi S, Mariani R, Calza S, Fracanzani AL, Modignani GL, Bertola F, Busti F, Trombini P, Fraquelli M, Forni GL, Girelli D, Fargion S, Specchia C, Piperno A (2012) CYBRD1 as a modifier gene that modulates iron phenotype in HFE p. C282Y homozygous patients. Haematologica 97:1818–1825
Pietrangelo A (2010) Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 139:393–408 408.e1-2
Rochette J, Le Gac G, Lassoued K, Ferec C, Robson KJ (2010) Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet 128:233–248
Steinbicker AU, Bartnikas TB, Lohmeyer LK, Leyton P, Mayeur C, Kao SM, Pappas AE, Peterson RT, Bloch DB, Yu PB, Fleming MD, Bloch KD (2011) Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood 118:4224–4230
Tanaka T, Roy CN, Yao W, Matteini A, Semba RD, Arking D, Walston JD, Fried LP, Singleton A, Guralnik J, Abecasis GR, Bandinelli S, Longo DL, Ferrucci L (2010) A genome-wide association analysis of serum iron concentrations. Blood 115:94–96
Tolosano E, Fagoonee S, Garuti C, Valli L, Andrews NC, Altruda F, Pietrangelo A (2005) Haptoglobin modifies the hemochromatosis phenotype in mice. Blood 105:3353–3355
van Dijk BA, Kemna EH, Tjalsma H, Klaver SM, Wiegerinck ET, Goossens JP, Slee PH, Breuning MH, Swinkels DW (2007) Effect of the new HJV-L165X mutation on penetrance of HFE. Blood 109:5525–5526
Waalen J, Nordestgaard BG, Beutler E (2005) The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol 18:203–220
Wang F, Paradkar PN, Custodio AO, McVey Ward D, Fleming MD, Campagna D, Roberts KA, Boyartchuk V, Dietrich WF, Kaplan J, Andrews NC (2007) Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet 39:1025–1032
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Delaby, C., Oustric, V., Schmitt, C. et al. Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice. Mamm Genome 24, 427–438 (2013). https://doi.org/10.1007/s00335-013-9479-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-013-9479-6