title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: University of Rennes, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Bardou-Jacquet
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Island
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Jouanolle
authors.forename: Lénaïck
authors.initials: L
authors.lastname: Détivaud
authors.forename: Nadia
authors.initials: N
authors.lastname: Fatih
authors.forename: Martine
authors.initials: M
authors.lastname: Ropert
authors.forename: Eolia
authors.initials: E
authors.lastname: Brissot
authors.forename: Annick
authors.initials: A
authors.lastname: Mosser
authors.forename: Hervé
authors.initials: H
authors.lastname: Maisonneuve
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000747:Anemia, Hypochromic / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D021381:Protein Transport; D059368:RNA Isoforms / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D059368:RNA Isoforms; D000099236:Solute Carrier Family 11, Member 2