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.

The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology

“…It is likely, as with Long QT syndrome, that given enough time and patients, KCNE2 polymorphisms associated with at least subclinical hypochlorhydria will emerge, and possibly rarely associate with familial gastric cancer particularly if homozygous recessive cases of KCNE2 loss-of-function mutations occur (as is observed for hearing loss in LQTS patients with KCNE1 mutations and Jervell and Lange-Nielsen syndrome). We also discovered, unsurprisingly because low gastric pH is required for efficient iron absorption, that Kcne2 −/− mice exhibit iron-deficiency anemia 47 , a finding later confirmed by others 51 . Again, it will be of interest to see whether human KCNE2 polymorphisms, as with KCNQ1, correlate with anemia.…”

Perturbations of serum electrolyte levels in iron deficiency anemia - A comparative analysis

“…The disruption of this regulatory subunit may also alter the levels of potassium in IDA. [4] This implies that IDA and serum potassium levels are interrelated with each other. Studies have revealed that electrolyte level alterations also occur in other types of anemia like sickle cell anemia and β-thalassemia.…”

“…[3] Iron is vital for human health and defects in iron homeostasis result in serious pathologic abnormalities such as hemochromatosis and anemia. [4] ID is the world's most widespread nutritional disorder, irrespective of age, gender, and socioeconomic status, affecting both industrialized and developing countries. In ID , there is insufficient iron to maintain normal physiologic functions.…”

Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia

“…Kcne2 deletion-linked achlorhydria 24 causes iron-deficiency anemia 12 30 , which can predispose to dyslipidemia and NAFLD 11 . Although data vary depending on the animal model studied, iron deficiency in rats, for example, has been reported to increase hepatic lipogenesis, causing steatosis; this may occur via increased de novo lipogenesis from glucose 31 .…”