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
Zugehörigkeit anzeigen +
Zeitschrift:
Nephrology Dialysis Transplantation

ISSN: 0931-0509,  1460-2385

Datum der Publikation: 2022

Ausgabe: 38

Nummer: 3

Seiten: 679-690

Art: Artikel

DOI: 10.1093/NDT/GFAC182 GOOGLE SCHOLAR lock_openOpen Access editor

Andere Publikationen in: Nephrology Dialysis Transplantation

Ziele für nachhaltige Entwicklung

Zusammenfassung

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.

€ Finanzierung ansehen

Informationen zur Finanzierung

Geldgeber

Bibliographische Referenzen

  • Schlingmann, (2002), Nat Genet, 31, pp. 166
  • Walder, (2002), Nat Genet, 31, pp. 171
  • Schlingmann, (2005), J Am Soc Nephrol, 16, pp. 3061
  • Li, (2006), J Gen Physiol, 127, pp. 525
  • Li, (2007), J Biol Chem, 282, pp. 25817
  • Chubanov, (2016), eLife, 5, pp. e20914
  • Ferioli, (2017), Sci Rep, 7, pp. 8806
  • Voets, (2004), J Biol Chem, 279, pp. 19
  • Mittermeier, (2019), Proc Natl Acad Sci USA, 116, pp. 4706
  • Robak, (2016), Arch Anim Breed, 59, pp. 267
  • de Baaij, (2012), Clin Kidney J, 5, pp. i15
  • de Baaij, (2015), Physiol Rev, 95, pp. 1
  • Lainez, (2014), Eur J Hum Genet, 22, pp. 497
  • Arjona, (2014), PLoS Genet, 10, pp. e1004267
  • Bockenhauer, (2009), N Engl J Med, 360, pp. 1960
  • de Baaij, (2015), Nephrol Dial Transplant, 30, pp. 952
  • Ferre, (2014), J Am Soc Nephrol, 25, pp. 574
  • Groenestege, (2007), J Clin Invest, 117, pp. 2260
  • Schlingmann, (2018), Am J Hum Genet, 103, pp. 808
  • Schlingmann, (2021), J Am Soc Nephrol, 32, pp. 1498
  • van der Wijst, (2018), Nephron, 139, pp. 359
  • Nadler, (2001), Nature, 411, pp. 590
  • Ryazanova, (2010), Nat Commun, 1, pp. 109
  • Chubanov, (2017), Cell Calcium, 67, pp. 166
  • Quitterer, (2001), J Biol Chem, 276, pp. 6763
  • Rodriguez-Ortiz, (2014), Nephrol Dial Transplant, 29, pp. 282
  • Karczewski, (2020), Nature, 581, pp. 434
  • Schaffers, (2018), Am J Physiol Renal Physiol, 314, pp. F1027
  • Thebault, (2009), J Am Soc Nephrol, 20, pp. 78
  • Nair, (2012), Proc Natl Acad Sci U S A, 109, pp. 11324
  • de Baaij, (2014), Pflugers Arch, 466, pp. 1941
  • Elizondo, (2010), Endocrinology, 151, pp. 5700
  • Schmitz, (2003), Cell, 114, pp. 191
  • Jin, (2008), Science, 322, pp. 756
  • Cartwright, (2020), Hum Mol Genet, 29, pp. 1797