Possible role for rareTRPM7variants in patients with hypomagnesaemia with secondary hypocalcaemia

Abstract

Background Hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder caused by pathogenic variants in TRPM6, encoding the channel-kinase Transient Receptor Potential Melastatin type 6. Patients have very low serum Mg2+ levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without diagnosis. Methods In this study, two families with a HSH phenotype but negative for TRPM6 pathogenic variants were subjected to whole exome sequencing. Using a complementary combination of biochemical and functional analyses in overexpression systems and patient-derived fibroblasts, the effect of the TRPM7 identified variants on Mg2+ transport was examined. Results For the first time, variants in TRPM7 were identified in two families as potential cause for hereditary hypomagnesemia with secondary hypocalcemia. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcemia. In the first family, a splice-site variant caused the incorporation of intron 1 sequences in the TRPM7 mRNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit reduced cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity. Conclusion We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesemia and secondary hypocalcemia. Screening of unresolved patients with hypomagnesemia and secondary hypocalcemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.

TRPM7 kinase mediates hypomagnesemia-induced seizure-related death

“…HypoMg has been long associated with increased seizure activities and epilepsy 1 – 4 , 37 . We have found that a low-Mg diet induces seizures and death, with female mice being more susceptible than males 11 .…”

“…Mutations in both TRPM6 and TRPM7 have been associated with HypoMg and seizures 2 , 4 , 5 . Moreover, Mg supplementation can prevent these seizures.…”

“…Hypomagnesemia (HypoMg, serum Mg < 0.7 mmol/L) is associated with afebrile seizures and epilepsy, especially in patients with mutations of magnesium (Mg) transporters such as transient receptor potential cation channel subfamily M 7 (TRPM7), TRPM6, and cyclin and CBS domain divalent metal cation transport mediator 2 (CNNM2) 1 – 5 . The mechanism for these seizures is unknown, but a role for low Mg is clear: long-term Mg supplementation shows significant protection for these patients against seizures, cognitive development, and motor development 1 – 4 .…”

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

“…Strikingly, the mortality rate of the pups can be decreased if dams are supplemented with Zn during pregnancy. Recently, human patients with rare mutations in Trpm7 were found in patients with hereditary hypomagnesemia with secondary hypocalcemia [427]. Patients suffered from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcemia.…”

A 26-Day-Old Neonate Presenting with Familial Hypomagnesemia with Secondary Hypocalcemia Associated with the Novel Homozygous TRPM6 Gene Variant c.5281C>G p. (Arg1761Gly) chr9: 77354845 – A Case Report

“…Gitelman syndrome, arising from SLC12A3 mutations, disrupts magnesium reabsorption, resulting in hypomagnesemia and hypercalciuria [ 3 ]. Hypocalciuric hypomagnesemia, attributed to mutations in the thick ascending limb of Henle, leads to hypercalciuric hypomagnesemia [ 4 ]. Furthermore, epilepsy, ataxia, sensorineural deafness (EAST) syndrome, stemming from KCNJ10 mutations, culminates in hypomagnesemia due to impaired Kir4.1 potassium channel function [ 6 , 7 ].…”