Genetics of Magnesium Disorders

Abstract

Background: Magnesium (Mg²⁺), the second most abundant cation in the cell, is woven into a multitude of cellular functions. Dysmagnesemia is associated with multiple diseases and, when severe, can be life-threatening. Summary: This review discusses Mg²⁺ homeostasis and function with specific focus on renal Mg²⁺ handling. Intrarenal channels and transporters related to Mg²⁺ absorption are discussed. Unraveling the rare genetic diseases with manifestations of dysmagnesemia has greatly increased our understanding of the complex and intricate regulatory network in the kidney, specifically, functions of tight junction proteins including claudin-14, -16, -19, and -10; apical ion channels including: TRPM6, K_v1.1, and ROMK; small regulatory proteins including AC3 and ANK3; and basolateral proteins including EGF receptor, γ-subunit (FXYD2) of Na-K-ATPase, K_ir4.1, CaSR, CNNM2, and SLC41A. Although our understanding of Mg²⁺ handling of the kidney has expanded considerably in the last two decades, many questions remain. Future studies are needed to elucidate a multitude of unknown aspects of Mg²⁺ handling in the kidney. Key Message: Understanding rare and genetic diseases of Mg²⁺ dysregulation has expanded our knowledge and furthers the development of strategies for preventing and managing dysmagnesemia.

Novel Aspects of Renal Magnesium Homeostasis

“…The Mg 2+ ions enter into the cell through the apical TRPM6 channel and are then extruded by either CNNM2 and/or SLC41A3 (still under debate). The apical force needed for Mg 2+ transport is created by the cooperative action of the basolateral Na + K + ATPase, the Cl - channel ClC-Kb, the K + transporter Kir 4.1 and the apical Na + Cl − cotransporter (NCC) and the K + extruders, ROMK and Kv 1.1 ( 5 , 27 ).…”

“…Here, apical uptake, intracellular buffering, transport, and the extrusion at the basolateral site is concerted by a highly defined and regulated (e.g., hormonal) molecular machinery that has been recently reviewed in Ref. ( 5 , 27 ). Among the eight different types of Mg 2+ transport factors identified in eukaryotes (TRPM6/M7, Mrs2, MMgT, MagT1, SLC41 family, NIPA, HIP14, and CNNMs) ( 61 – 67 ), only three are expressed at the DCT.…”

“…Mg 2+ has also been identified as a second messenger, e.g., in T-Cells, where mutations in the gene MAGT1 have been linked to human immunodeficiency. There, mutations disable transient Mg 2+ influx induced by the activation of the T-cell receptor ( 5 ).…”

Acid-Base and Electrolyte Disorders in Patients with and without Chronic Kidney Disease: An Update

“…In the DCT, Mg 2+ reabsorption is transcellular via TRPM6, driven by the transapical membrane potential. As this is the last part of the renal tubular Mg 2+ absorption and there is a steep transepithelial Mg 2+ concentration gradient, the transapical membrane potential is tightly regulated through multitudes of channels and transporter proteins, detailed in a recent review [45] . Both hypermagnesemia (>2.3 mg/dL) and hypomagnesemia (<1.7 mg/dL) are relatively common with reported prevalence of 31 and 20%, respectively, in hospitalized patients [46] .…”

Dietary Magnesium Supplements – Is there any Problem?

“…The genetic background of Mg dysregulation is heterogeneous and complex in addition their detection is difficult therefore these alterations on population-level are unpredictable. For instance in case of magnesium-treatment of hypertension we see high variability in effectiveness: good success rate in certain patient groups (high responders) in comparison to others [76,77].…”