Magnesium Homeostasis: Lessons from Human Genetics

Abstract

Mg 2+ , the fourth most abundant cation in the body, serves as a cofactor for about 600 cellular enzymes. One third of ingested Mg 2+ is absorbed from the gut through a saturable transcellular process and a concentration-dependent paracellular process. Absorbed Mg 2+ is excreted by the kidney and maintains serum Mg 2+ within a narrow range of 0.7-1.25 mmol/L. The reabsorption of Mg 2+ by the nephron is characterized by paracellular transport in the proximal tubule and thick ascending limb. The nature of the transport pathways in the gut epithelia and thick ascending limb has emerged from an understanding of the molecular mechanisms responsible for rare monogenetic disorders presenting with clinical hypomagnesemia. These human disorders due to loss-of-function mutations, in concert with mouse models, have led to a deeper understanding of Mg 2+ transport in the gut and renal tubule. This review focuses on the nature of the transporters and channels revealed by human and mouse genetics and how they are integrated into an understanding of human Mg 2+ physiology.

Figure 1

Nature of transport processes in the gut. In the gastrointestinal tract, predominantly the small intestine reabsorbs Mg²⁺ by two distinct processes. There is a saturable transcellular process that is engaged at low to normal Mg²⁺ intake and a concentration-dependent paracellular absorptive process at which high oral Mg²⁺ intake becomes the major route of intestinal absorption. These combined processes result in absorption of about one third of oral ingestion of Mg²⁺.

Figure 2

Detailed mechanisms of gastrointestinal transcellular absorption. In the gut lumen, the apical entry step for transcellular transport is mediated by TRPM6/7, which is mutated in hypomagnesemia with secondary hypocalcemia (HSH) resulting in loss of function and contributing to the hypomagnesemia phenotype in this syndrome. For the basolateral exit step, several candidates have emerged. Experimental studies in Cnnm4^−/− mice show that these animals express hypomagnesemia and excrete high levels of Mg²⁺ in feces. In addition, Cnnm2+/− mice have higher Mg²⁺ in stools when compared with wild-type Cnnm2+/+ mice. In mice, Slc41a1 and Slc41a3 do not appear to play a critical role in intestinal Mg²⁺ absorption; however, we have limited information on the potential role of Slc41a2. All three variants are expressed in the intestine. The molecular nature of the players involved in paracellular transport is unclear.

Figure 3

Essential features of paracellular Mg²⁺ reabsorption in TALH. The cortical TALH cell tight junctions are constituted by a heterodimer of claudin-16 and claudin-19, which form the nonselective cation channel. The transmembrane potential is generated by the movement of Na⁺ through the channel driven by the concentration gradient (interstitium>tubular lumen). Impairment of transmembrane potential can occur with loss of function of NKCC2, decreased ROMK, and CLC-Kb activity, all of which increase luminal Na⁺ concentration and decrease transmembrane potential. The CaSR inhibits ROMK through formation of 20-HETE acid and increases claudin-14 expression. 20-HETE, 20-hydroxyeicatetraenoic; CaSR, calcium-sensing receptor; ROMK, renal outer medullary K1; TALH, thick ascending limb of Henle.

Figure 4

Regulation of apical Mg²⁺ entry in the distal convoluted tubule. In the distal convoluted tubule, TRPM6/7 is the rate-limiting pore for Mg²⁺ entry. Loss-of-function mutations in TRPN6 cause HSH, a severe form of hypomagnesemia presenting in early life. The apical expression of TRPM6 is regulated by EGF/EGFR, which promotes apical TRPM6 expression by modulating vesicular trafficking, and loss of EGF results in downregulation of apical TRPM6. Loss-of-function mutations or inhibition in NCC on the apical membrane cause a downregulation of TRPM6 through distal convoluted tubule atrophy. Finally, the driving force for Mg²⁺ absorption is the transmembrane potential generated by K⁺ extrusion through Kv1.1. Loss-of-function mutations in KCNA1, gene encoding Kv1.1, causes isolated autosomal dominant hypomagnesemia. DCT, distal convoluted tubule; EGFR, epidermal growth factor receptor.

Figure 5

Potential players involved in the distal convoluted tubule exit step for Mg²⁺. Loss of functions in the gene for the γ-subunit of Na⁺-K⁺-ATPase (FXYD2) is associated with autosomal dominant hypomagnesemia. HNF1B, a transcription factor, positively stimulates FXYD2 expression in concert with PCBD1, and mutations in the genes for HNF1B and PCBD1 are associated with hypomagnesemia. It is possible that autosomal dominant mutations in FXYD2 and HNF1B affect Na⁺-K⁺-ATPase function, causing dysregulation of ionic concentrations favoring the exit of Mg²⁺ through the basolateral membrane. ARL 15, the negative regulator of CNNM2, is shown. Loss-of-function mutations in Kir4.1/5.1 lead to downregulation of NCC and loss of TRPM6 and tubular atrophy. The nature of the exit pore has not been determined with certainty, but several potential candidates have emerged from identified human gene mutations and evidence from knockout mouse models. These include SLC41A3 and CNNM2.