Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia

Abstract

Iron homeostasis is a dynamic process that is tightly controlled to balance iron uptake, storage, and export. Reduction of dietary iron from the ferric to the ferrous form is required for uptake by solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 (Slc11a2) into the enterocytes. Both processes are proton dependent and have led to the suggestion of the importance of acidic gastric pH for the absorption of dietary iron. Potassium voltage-gated channel subfamily E, member 2 (KCNE2), in combination with potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1), form a gastric potassium channel essential for gastric acidification. Deficiency of either Kcne2 or Kcnq1 results in achlorhydia, gastric hyperplasia, and neoplasia, but the impact on iron absorption has not, to our knowledge, been investigated. Here we report that Kcne2-deficient mice, in addition to the previously reported phenotypes, also present with iron-deficient anemia. Interestingly, impaired function of KCNQ1 results in iron-deficient anemia in Jervell and Lange-Nielsen syndrome patients. We speculate that impaired function of KCNE2 could result in the same clinical phenotype.

Figure 1

Altered hematologic parameters in Kcne2^tm1a/tm1a mutants. (A) Red blood cell count, (B) hemoglobin, (C) hematocrit, (D) mean corpuscular hemoglobin, (E) red blood cell distribution width, (F) mean corpuscular volume, and (G) platelet count were all determined at 16 weeks of age. For male control versus male Kcne2^tm1a/tm1a mice, p values are indicated with the boxplots showing the mean interquartile range, with whiskers to the 2.5 and 97.5 percentiles and dots for outliers. For all graphs, n = 7 for female Kcne2^tm1a/tm1a mutants, n = 187 for female controls, n = 7 for male Kcne2^tm1a/tm1a mutants, and n = 202 for male controls.

Figure 2

Altered plasma chemistry parameters in Kcne2^tm1a/tm1a mutants. (A) Iron, (B) ferritin, (C) transferrin/log₁₀(ferritin) ratio, (D) erythropoietin, and (E) magnesium were all determined at 16 weeks of age. For the genotype effect of male control versus male Kcne2^tm1a/tm1a mice, p values are indicated with boxplots showing the mean interquartile range, with whiskers to the 2.5 and 97.5 percentiles and dots for outliers. For iron, magnesium, ferritin, and transferrin, n = 7 for Kcne2^tm1a/tm1a female and male mutants; for erythropoietin, n = 5 for female and n = 6 for male Kcne2^tm1a/tm1a mutants. For iron and magnesium, n = 186 female and n = 202 male controls. For erythropoietin, n = 19 female and n = 21 male controls; for ferritin, n = 21 female and n = 23 male controls; for transferrin, n = 22 for female and n = 23 for male controls. (F) Presence of a gastric adenoma (surrounded by the box), with architectural and nuclear atypia typical of a dysplastic adenoma, in a male Kcne2^tm1a/tm1a mutant. In male Kcne2^tm1a/tm1a mutants, we observed reduced iron content in spleen, as detected by Perls' Prussian blue stain; shown are representative images from (G) a male control and (H) a male Kcne2^tm1a/tm1a mutant.

Figure 2

Altered plasma chemistry parameters in Kcne2^tm1a/tm1a mutants. (A) Iron, (B) ferritin, (C) transferrin/log₁₀(ferritin) ratio, (D) erythropoietin, and (E) magnesium were all determined at 16 weeks of age. For the genotype effect of male control versus male Kcne2^tm1a/tm1a mice, p values are indicated with boxplots showing the mean interquartile range, with whiskers to the 2.5 and 97.5 percentiles and dots for outliers. For iron, magnesium, ferritin, and transferrin, n = 7 for Kcne2^tm1a/tm1a female and male mutants; for erythropoietin, n = 5 for female and n = 6 for male Kcne2^tm1a/tm1a mutants. For iron and magnesium, n = 186 female and n = 202 male controls. For erythropoietin, n = 19 female and n = 21 male controls; for ferritin, n = 21 female and n = 23 male controls; for transferrin, n = 22 for female and n = 23 for male controls. (F) Presence of a gastric adenoma (surrounded by the box), with architectural and nuclear atypia typical of a dysplastic adenoma, in a male Kcne2^tm1a/tm1a mutant. In male Kcne2^tm1a/tm1a mutants, we observed reduced iron content in spleen, as detected by Perls' Prussian blue stain; shown are representative images from (G) a male control and (H) a male Kcne2^tm1a/tm1a mutant.