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Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice

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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.

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Authors and Affiliations

  1. INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, BP 416, 75018, Paris, France

    Laurent Gouya

  2. INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris 7 Denis Diderot, site Bichat, BP 416, 75018, Paris, France

    Constance Delaby, Vincent Oustric, Caroline Schmitt, Francoise Muzeau, Anne-Marie Robreau, Philippe Letteron, Eric Couchi, Angel Yu, Saïd Lyoumi, Jean-Charles Deybach, Herve Puy, Zoubida Karim, Carole Beaumont & Bernard Grandchamp

  3. AP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, 92700, Colombes, France

    Constance Delaby, Vincent Oustric, Caroline Schmitt, Anne-Marie Robreau, Jean-Charles Deybach, Herve Puy & Laurent Gouya

  4. Université Versailles Saint Quentin en Yvelines, 78000, Versailles, France

    Saïd Lyoumi & Laurent Gouya

  5. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Peter Demant

  6. AP-HP, Service de Biochimie, Endocrinologie et Génétique Moléculaire Hôpital Ambroise Paré, 92000, Boulogne-Billancourt, France

    Laurent Gouya

  7. CHU de Montpellier - Hôpital St. Eloi, Institut de Recherches en Biothérapie (IRB), Biochimie - Protéomique Clinique, 80, avenue A. Fliche, 34295 , Montpellier Cedex 5, France

    Constance Delaby

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  1. Constance Delaby
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  2. Vincent Oustric
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  3. Caroline Schmitt
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  4. Francoise Muzeau
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  7. Eric Couchi
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  8. Angel Yu
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Correspondence to Laurent Gouya.

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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

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