Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
Por:
Vargas-Poussou, R, Claverie-Martin, F, Prot-Bertoye, C, Carotti, V, van der Wijst, J, Perdomo-Ramirez, A, Fraga-Rodriguez, GM, Hureaux, M, Bos, C, Latta, F, Houillier, P, Hoenderop, JGJ, de Baaij, JHF
Publicada:
28 feb 2023
Ahead of Print:
1 may 2022
Resumen:
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.
Filiaciones:
Vargas-Poussou, R:
Hop Europe Georges Pompidou, Dept Genet, Ctr Reference Malad Renales Hereditaires Enfant A, Paris, France
Claverie-Martin, F:
Hosp Univ Nuestra Senora de Candelaria, Renal Tube Grp, Unidad Invest, Santa Cruz De Tenerife, Spain
Prot-Bertoye, C:
Univ Paris, CNRS, INSERM, Ctr Rech Cordeliers,Sorbonne Univ, Paris, France
Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Physiol, Paris, France
Ctr Reference Malad Renales Hereditaires Enfant A, Paris, France
Carotti, V:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
van der Wijst, J:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
Perdomo-Ramirez, A:
Hosp Univ Nuestra Senora de Candelaria, Renal Tube Grp, Unidad Invest, Santa Cruz De Tenerife, Spain
Fraga-Rodriguez, GM:
Hosp Santa Creu & Sant Pau, Secc Nefrol Pediat, Barcelona, Spain
Hureaux, M:
Hop Europe Georges Pompidou, Dept Genet, Ctr Reference Malad Renales Hereditaires Enfant A, Paris, France
Bos, C:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
Latta, F:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
Houillier, P:
Univ Paris, CNRS, INSERM, Ctr Rech Cordeliers,Sorbonne Univ, Paris, France
Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Physiol, Paris, France
Ctr Reference Malad Renales Hereditaires Enfant A, Paris, France
Hoenderop, JGJ:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
de Baaij, JHF:
Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Physiol, Med Ctr, Nijmegen, Netherlands
hybrid, Green Published
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