Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model

PLoS Genet. 2013;9(12):e1003983. doi: 10.1371/journal.pgen.1003983. Epub 2013 Dec 5.

Abstract

Transcellular Mg(2+) transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg(2+) extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg(2+) extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg(2+) by exchanging intracellular Mg(2+) with extracellular Na(+). Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg(2+) extrusion activity. These results demonstrate the crucial importance of Mg(2+) extrusion by CNNM4 in organismal and topical regulation of magnesium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amelogenesis Imperfecta / genetics*
  • Amelogenesis Imperfecta / pathology
  • Animals
  • Biological Transport / genetics
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Disease Models, Animal
  • Epithelium / metabolism
  • Humans
  • Hypertrichosis / genetics*
  • Hypertrichosis / pathology
  • Leber Congenital Amaurosis / genetics*
  • Leber Congenital Amaurosis / pathology
  • Magnesium / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation, Missense
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology

Substances

  • CNNM4 protein, human
  • Cation Transport Proteins
  • Magnesium

Supplementary concepts

  • Amaurosis hypertrichosis

Grants and funding

This work was supported by the Funding Program for Next Generation World-Leading Researchers from the Japan Society for the Promotion of Science (JSPS) to HM (LS083, http://www.jsps.go.jp/j-jisedai/), Exciting Leading-Edge Research Projects from Osaka University to HM (http://www.osaka-u.ac.jp/ja/research/researcher_sp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.