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