| Autor: |
Vargas-Poussou, Rosa, Claverie-Martin, Felix, Prot-Bertoye, Caroline, Carotti, Valentina, van der Wijst, Jenny, Perdomo-Ramirez, Ana, Fraga-Rodriguez, Gloria M, Hureaux, Marguerite, Bos, Caro, Latta, Femke, Houillier, Pascal, Hoenderop, Joost G J, Baaij, Jeroen H F de |
| Předmět: |
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| Zdroj: |
Nephrology Dialysis Transplantation; Mar2023, Vol. 38 Issue 3, p679-690, 12p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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