Possible role for rare TRPM7 variants in patients with hypomagnesemia with secondary hypocalcemia

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.

HSH; TRPM6; TRPM7; genetics; magnesium deficiency.