Patients with hypomagnesaemia (serum Mg2+ < 0.7 mmol/L) suffer from a wide range of symptoms including muscle cramps, cardiac arrhythmias and epilepsy. Hypomagnesaemia has been associated to several neurological diseases. Disturbances in the body Mg2+ homeostasis can often be attributed to a reduced Mg2+ absorption in the distal convoluted tubule (DCT) segment of the kidney. The DCT determines the urinary Mg2+ excretion, since no reabsorption takes place beyond this segment of the nephron. In this lecture, I aim to show the recent identification of novel genes regulating Mg2+ transport.
I’ll report the identification of novel mutations in the DCT-protein CNNM2 in five families suffering from intellectual disability, seizures, and hypomagnesaemia. To elucidate the physiological role of CNNM2, CNNM2 function was studied in in vitro transport assays and the zebrafish knockdown model system. Using stable Mg2+ isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg2+ uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development and reduced body Mg content. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. Altogether these data show that CNNM2 is fundamental for brain development, neurological functioning and Mg2+ homeostasis.