A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload
| Autor: | Lénaïck Détivaud, Olivier Loréal, Eolia Brissot, Anne-Marie Jouanolle, Nadia Fatih, Pierre Brissot, Marie-Laure Island, Annick Mosser, Martine Ropert, Hervé Maisonneuve, Edouard Bardou-Jacquet |
|---|---|
| Přispěvatelé: | Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie [CHU Rennes], Centre Hospitalier Universitaire [Rennes], Centre de Référence des surcharges en Fer rares d'origine génétique, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], CHU Pontchaillou [Rennes], laboratoire de Biochimie Générale et Enzymologie, Hôpital Pontchaillou, Service d'hématologie, Centre hospitalier La Roche-Sur-Yon, the French National Academy of Medicine, the LSHM-CT-2006-037296 European Community Grant (Euroiron1), the Association Fer et Foie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire de Génétique Moléculaire et Hormonologie |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
MESH: Sequence Analysis
DNA Microcytic anemia MESH: Anemia Hypochromic medicine.disease_cause 0302 clinical medicine RNA Isoforms Cation Transport Proteins DMT1 Anemia Hypochromic 0303 health sciences Mutation biology MESH: Alternative Splicing digestive oral and skin physiology Anemia Hematology MESH: Amino Acid Substitution 3. Good health Protein Transport Liver 030220 oncology & carcinogenesis RNA splicing Molecular Medicine Female Hemochromatosis Adult Gene isoform MESH: Protein Transport Iron Overload MESH: Mutation Iron Cell Line 03 medical and health sciences MESH: Cation Transport Proteins MESH: Iron Overload medicine Humans Molecular Biology Gene 030304 developmental biology MESH: Humans MESH: Adult [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Sequence Analysis DNA Cell Biology medicine.disease Molecular biology MESH: RNA Isoforms MESH: Cell Line Ferritin Alternative Splicing Amino Acid Substitution biology.protein MESH: Female MESH: Liver |
| Zdroj: | Blood Cells, Molecules and Diseases Blood Cells, Molecules and Diseases, 2011, 47 (4), pp.243-8. ⟨10.1016/j.bcmd.2011.07.004⟩ Blood Cells, Molecules and Diseases, Elsevier, 2011, 47 (4), pp.243-8. ⟨10.1016/j.bcmd.2011.07.004⟩ |
| ISSN: | 1079-9796 1096-0961 |
| DOI: | 10.1016/j.bcmd.2011.07.004⟩ |
| Popis: | International audience; BACKGROUND: DMT1 is a transmembrane iron transporter involved in iron duodenal absorption and cellular iron uptake. Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia and hepatic iron overload, with unexpectedly low levels of plasma ferritin in the presence of iron stores. DESIGN AND METHODS: We report a patient with a similar phenotype due to two mutations in the SLC11A2 gene, the known p.Gly212Val (G212V) mutation and a novel one, p.Asn491Ser (N491S). To assess the expression of DMT1 in human liver, we studied the expression of the four DMT1 mRNA isoforms by real-time quantitative PCR in control human liver samples. We also studied the effect of G212V and N491S DMT1 mutations on RNA splicing in blood leukocytes and cellular trafficking of dsRed2-tagged-DMT1 protein in the human hepatic cell line HuH7. RESULTS: Our results showed that i) only the isoforms 1B-IRE and 1B-nonIRE were significantly expressed in human liver; ii) the G212V mutation did not seem to affect mRNA splicing and the N491S mutation induced a splicing alteration leading to a truncated protein, which seemed quantitatively of low relevance; and iii) the N491S mutation, in contrast to the G212V mutation, led to abnormal protein trafficking. CONCLUSIONS: Our data confirm the major role of DMT1 in the maintenance of iron homeostasis in humans and demonstrate that the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect