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

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...

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Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p12054
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12054
Access Level:acceso abierto
Palabra clave:genetics
HSH
magnesium deficiency
TRPM6
TRPM7
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spelling Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemiaVargas-Poussou, RClaverie-Martin, FProt-Bertoye, CCarotti, Vvan der Wijst, JPerdomo-Ramirez, AFraga-Rodriguez, GMHureaux, MBos, CLatta, FHouillier, PHoenderop, JGJde Baaij, JHFgeneticsHSHmagnesium deficiencyTRPM6TRPM7Background 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.OXFORD UNIV PRESS2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12054NEPHROLOGY DIALYSIS TRANSPLANTATIONISSN: 09310509ISSNe: 14602385reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p120542026-06-14T12:41:47Z
dc.title.none.fl_str_mv Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
title Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
spellingShingle Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
Vargas-Poussou, R
genetics
HSH
magnesium deficiency
TRPM6
TRPM7
title_short Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
title_full Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
title_fullStr Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
title_full_unstemmed Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
title_sort Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia
dc.creator.none.fl_str_mv 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
author Vargas-Poussou, R
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv genetics
HSH
magnesium deficiency
TRPM6
TRPM7
topic genetics
HSH
magnesium deficiency
TRPM6
TRPM7
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12054
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12054
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv OXFORD UNIV PRESS
publisher.none.fl_str_mv OXFORD UNIV PRESS
dc.source.none.fl_str_mv NEPHROLOGY DIALYSIS TRANSPLANTATION
ISSN: 09310509
ISSNe: 14602385
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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