Identification of a Steap3 endosomal targeting motif essential for normal iron metabolism

Blood. 2009 Feb 19;113(8):1805-8. doi: 10.1182/blood-2007-11-120402. Epub 2008 Oct 27.

Abstract

Hereditary forms of iron-deficiency anemia, including animal models, have taught us much about the normal physiologic control of iron metabolism. However, the discovery of new informative mutants is limited by the natural mutation frequency. To address this limitation, we have developed a screen for heritable abnormalities of red blood cell morphology in mice with single-nucleotide changes induced by the chemical mutagen ethylnitrosourea (ENU). We now describe the first strain, fragile-red, with hypochromic microcytic anemia resulting from a Y228H substitution in the ferrireductase Steap3 (Steap3(Y288H)). Analysis of the Steap3(Y288H) mutant identifies a conserved motif required for targeting Steap3 to internal compartments and highlights how phenotypic screens linked to mutagenesis can identify new functional variants in erythropoiesis and ascribe function to previously unidentified motifs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Iron-Deficiency / genetics*
  • Anemia, Iron-Deficiency / metabolism*
  • Anemia, Iron-Deficiency / physiopathology
  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Endosomes / metabolism
  • FMN Reductase / metabolism
  • Gene Library
  • Genetic Testing / methods
  • Humans
  • Iron / metabolism*
  • Kidney / cytology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagenesis
  • Oxidoreductases

Substances

  • Cell Cycle Proteins
  • Membrane Proteins
  • Iron
  • Oxidoreductases
  • TSAP6 protein, mouse
  • FMN Reductase
  • ferric citrate iron reductase