Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia.

Abstract

BACKGROUND:

Hypomagnesaemia with secondary hypocal-caemia (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 magnesium (Mg2+) levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without a diagnosis.

METHODS:

In this study, two families with an 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 a potential cause for hereditary HSH. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcaemia. In the first family, a splice site variant caused the incorporation of intron 1 sequences into the TRPM7 messenger RNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit decreased cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity.

CONCLUSIONS:

We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesaemia and secondary hypocalcaemia. Screening of unresolved patients with hypocalcaemia and secondary hypocalcaemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.

• Authors: Rosa Vargas-Poussou, Felix Claverie-Martin, Caroline Prot-Bertoye, Valentina Carotti, Jenny van der Wijst, Ana Perdomo-Ramirez, Gloria M Fraga-Rodriguez, Marguerite Hureaux, Caro Bos, Femke Latta, Pascal Houillier, Joost G J Hoenderop, Jeroen H F de Baaij
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 38 Issue 3 Pg. 679-690 (02 28 2023) ISSN: 1460-2385 [Electronic] England
• PMID: 35561741 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.

Chemical References

• Magnesium
• TRPM Cation Channels
• TRPM7 protein, human
• Protein Serine-Threonine Kinases

Topics

• Humans
• Magnesium
• Hypocalcemia
• TRPM Cation Channels (metabolism)
• Muscle Cramp (complications)
• Protein Serine-Threonine Kinases (metabolism)