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

Autor:	Vargas-Poussou R; Département de Génétique, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Hôpital Européen Georges Pompidou, Paris, France., Claverie-Martin F; Unidad de Investigación, Renal Tube Group, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain., Prot-Bertoye C; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, CNRS, Paris, France.; Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France., Carotti V; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., van der Wijst J; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Perdomo-Ramirez A; Unidad de Investigación, Renal Tube Group, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain., Fraga-Rodriguez GM; Sección de Nefrología Pediátrica, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain., Hureaux M; Département de Génétique, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Hôpital Européen Georges Pompidou, Paris, France., Bos C; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Latta F; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Houillier P; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, CNRS, Paris, France.; Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France., Hoenderop JGJ; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., de Baaij JHF; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2023 Feb 28; Vol. 38 (3), pp. 679-690.
DOI:	10.1093/ndt/gfac182
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. (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
Databáze:	MEDLINE
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