Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice

Blood. 2011 Dec 8;118(24):6418-25. doi: 10.1182/blood-2011-04-350082. Epub 2011 Oct 5.


Iron is an essential component of heme and hemoglobin, and therefore restriction of iron availability directly limits erythropoiesis. In the present study, we report a defect in iron absorption that results in iron-deficiency anemia, as revealed by an N-ethyl-N-nitrosourea-induced mouse phenotype called sublytic. Homozygous sublytic mice develop hypochromic microcytic anemia with reduced osmotic fragility of RBCs. The sublytic phenotype stems from impaired gastrointestinal iron absorption caused by a point mutation of the gastric hydrogen-potassium ATPase α subunit encoded by Atp4a, which results in achlorhydria. The anemia of sublytic homozygotes can be corrected by feeding with a high-iron diet or by parenteral injection of iron dextran; rescue can also be achieved by providing acidified drinking water to sublytic homozygotes. These findings establish the necessity of the gastric proton pump for iron absorption and effective erythropoiesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Achlorhydria / metabolism
  • Achlorhydria / physiopathology
  • Achlorhydria / therapy
  • Amino Acid Substitution
  • Anemia, Iron-Deficiency / diet therapy
  • Anemia, Iron-Deficiency / etiology*
  • Anemia, Iron-Deficiency / prevention & control
  • Animals
  • Disease Models, Animal
  • Ethylnitrosourea / pharmacology
  • Female
  • H(+)-K(+)-Exchanging ATPase / chemistry
  • H(+)-K(+)-Exchanging ATPase / genetics
  • H(+)-K(+)-Exchanging ATPase / metabolism*
  • Intestinal Absorption
  • Iron, Dietary / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagens / pharmacology
  • Osmotic Fragility
  • Point Mutation*
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Stomach / enzymology*
  • Stomach / pathology


  • Iron, Dietary
  • Mutagens
  • Protein Subunits
  • H(+)-K(+)-Exchanging ATPase
  • Ethylnitrosourea