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

Abstract

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.

• Authors: Lara Krieg, Oren Milstein, Philippe Krebs, Yu Xia, Bruce Beutler, Xin Du
• Journal: Blood (Blood) Vol. 118 Issue 24 Pg. 6418-25 (Dec 08 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21976678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Achlorhydria (metabolism, physiopathology, therapy)
• Amino Acid Substitution
• Anemia, Iron-Deficiency (diet therapy, etiology, prevention & control)
• Animals
• Disease Models, Animal
• Ethylnitrosourea (pharmacology)
• Female
• H(+)-K(+)-Exchanging ATPase (chemistry, genetics, 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, genetics, metabolism)
• Stomach (enzymology, pathology)