title: Contributions of beta2-microglobulin-dependent molecules and lymphocytes to iron regulation: insights from HfeRag1(-/-) and beta2mRag1(-/-) double knock-out mice.
abstract: Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a beta2-microglobulin (beta2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of beta2mRag1(-/-) double-deficient mice, lacking all beta2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with beta2m single knock-out mice. To evaluate whether the observed phenotype in beta2mRag1(-/-) mice was due solely to the absence of Hfe or to other beta2m-dependent molecules, we generated HfeRag1(-/-) double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with beta2mRag1(-/-) mice. These results suggest that other beta2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity.
authors.affiliation: Centre de recherche, Centre Hospitalier de l'Université de Montréal, QC, Canada.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.forename: Hortence
authors.initials: H
authors.lastname: Makui
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000818:Animals; D016654:Genes, RAG-1; D006432:Hemochromatosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008214:Lymphocytes / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D001613:beta 2-Microglobulin; C064658:RAG-1 protein; D007501:Iron