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

  1. Vargas-Poussou, Rosa 3
  2. Claverie-Martin, Felix 4
  3. Prot-Bertoye, Caroline 567
  4. Carotti, Valentina 1
  5. van der Wijst, Jenny 1
  6. Perdomo-Ramirez, Ana 4
  7. Fraga-Rodriguez, Gloria M 2
  8. Hureaux, Marguerite 3
  9. Bos, Caro 1
  10. Latta, Femke 1
  11. Houillier, Pascal 567
  12. Hoenderop, Joost G J 1
  13. de Baaij, Jeroen H F 1
  1. 1 Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands
  2. 2 Sección de Nefrología Pediátrica, Hospital de la Santa Creu I Sant Pau , Barcelona , Spain
  3. 3 Département de Génétique, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Hôpital Européen Georges Pompidou , Paris , France
  4. 4 Unidad de Investigación, Renal Tube Group, Hospital Universitario Nuestra Señora de Candelaria , Santa Cruz de Tenerife , Spain
  5. 5 Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, CNRS , Paris , France
  6. 6 Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou , Paris , France
  7. 7 Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte , Paris , France
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Revista:
Nephrology Dialysis Transplantation

ISSN: 0931-0509,  1460-2385

Año de publicación: 2022

Volumen: 38

Número: 3

Páginas: 679-690

Tipo: Artículo

DOI: 10.1093/NDT/GFAC182 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Nephrology Dialysis Transplantation

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Resumen

ABSTRACTBackgroundHypomagnesaemia 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.MethodsIn 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.ResultsFor 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.ConclusionsWe 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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