Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
Vargas-Poussou, Rosa (Hôpital Européen Georges Pompidou (París, França))
Claverie-Martin, F. (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))
Prot-Bertoye, C. (Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte)
Carotti, V. (Radboud University Medical Center)
Van Der Wijst, J. (Radboud University Medical Center)
Perdomo-Ramirez, A. (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))
Fraga Rodríguez, Gloria María (Institut d'Investigació Biomèdica Sant Pau)
Hureaux, M. (Hôpital Européen Georges Pompidou (París, França))
Bos, C. (Radboud University Medical Center)
Latta, F. (Radboud University Medical Center)
Houillier, Pascal (Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte)
Hoenderop, J.G.J. (Radboud University Medical Center)
De Baaij, J.H.F. (Radboud University Medical Center)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	Hypomagnesaemia with secondary hypocalcaemia (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. 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. 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. 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.
Ajuts:	Instituto de Salud Carlos III PI17/00153
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	TRPM6 ; TRPM7 ; HSH ; Genetics ; Magnesium deficiency
Publicat a:	Nephrology Dialysis Transplantation, Vol. 38 Núm. 3 (january 2023) , p. 679-690, ISSN 1460-2385

DOI: 10.1093/ndt/gfac182
PMID: 35561741

12 p, 1.7 MB

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