Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants

Willem Bosman; Gijs A.C. Franken; Javier de las Heras; Leire Madariaga; Tahsin Stefan Barakat; Rianne Oostenbrink; Marjon van Slegtenhorst; Ana Perdomo-Ramírez; Félix Claverie-Martín; Albertien M. van Eerde; Rosa Vargas-Poussou; Laurence Derain Dubourg; Irene González-Recio; Luis Alfonso Martínez-Cruz; Jeroen H.F. de Baaij; Joost G.J. Hoenderop

doi:10.1038/s41598-024-57061-7

Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants

Willem Bosman, Gijs A.C. Franken, Javier de las Heras, Leire Madariaga, Tahsin Stefan Barakat, Rianne Oostenbrink, Marjon van Slegtenhorst, Ana Perdomo-Ramírez, Félix Claverie-Martín, Albertien M. van Eerde, Rosa Vargas-Poussou, Laurence Derain Dubourg, Irene González-Recio, Luis Alfonso Martínez-Cruz, Jeroen H.F. de Baaij, Joost G.J. Hoenderop^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg²⁺ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca²⁺ homeostasis.

Original language	English
Article number	6917
Number of pages	13
Journal	Scientific Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-57061-7
Publication status	Published - 22 Mar 2024

Keywords

CNNM2
Genetic hypomagnesaemia
Intellectual disability
Variant characterisation

Access to Document

10.1038/s41598-024-57061-7Licence: CC BY

s41598-024-57061-7Final published version, 4.89 MBLicence: CC BY

Cite this

Bosman, W., Franken, G. A. C., de las Heras, J., Madariaga, L., Barakat, T. S., Oostenbrink, R., van Slegtenhorst, M., Perdomo-Ramírez, A., Claverie-Martín, F., van Eerde, A. M., Vargas-Poussou, R., Dubourg, L. D., González-Recio, I., Martínez-Cruz, L. A., de Baaij, J. H. F., & Hoenderop, J. G. J. (2024). Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants. Scientific Reports, 14(1), Article 6917. https://doi.org/10.1038/s41598-024-57061-7

@article{cb8ff667f9914adf98f548ae2f269168,

title = "Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants",

abstract = "Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.",

keywords = "CNNM2, Genetic hypomagnesaemia, Intellectual disability, Variant characterisation",

author = "Willem Bosman and Franken, {Gijs A.C.} and {de las Heras}, Javier and Leire Madariaga and Barakat, {Tahsin Stefan} and Rianne Oostenbrink and {van Slegtenhorst}, Marjon and Ana Perdomo-Ram{\'i}rez and F{\'e}lix Claverie-Mart{\'i}n and {van Eerde}, {Albertien M.} and Rosa Vargas-Poussou and Dubourg, {Laurence Derain} and Irene Gonz{\'a}lez-Recio and Mart{\'i}nez-Cruz, {Luis Alfonso} and {de Baaij}, {Jeroen H.F.} and Hoenderop, {Joost G.J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = mar,

day = "22",

doi = "10.1038/s41598-024-57061-7",

language = "English",

volume = "14",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Bosman, W, Franken, GAC, de las Heras, J, Madariaga, L, Barakat, TS, Oostenbrink, R, van Slegtenhorst, M, Perdomo-Ramírez, A, Claverie-Martín, F, van Eerde, AM, Vargas-Poussou, R, Dubourg, LD, González-Recio, I, Martínez-Cruz, LA, de Baaij, JHF & Hoenderop, JGJ 2024, 'Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants', Scientific Reports, vol. 14, no. 1, 6917. https://doi.org/10.1038/s41598-024-57061-7

TY - JOUR

T1 - Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants

AU - Bosman, Willem

AU - Franken, Gijs A.C.

AU - de las Heras, Javier

AU - Madariaga, Leire

AU - Barakat, Tahsin Stefan

AU - Oostenbrink, Rianne

AU - van Slegtenhorst, Marjon

AU - Perdomo-Ramírez, Ana

AU - Claverie-Martín, Félix

AU - van Eerde, Albertien M.

AU - Vargas-Poussou, Rosa

AU - Dubourg, Laurence Derain

AU - González-Recio, Irene

AU - Martínez-Cruz, Luis Alfonso

AU - de Baaij, Jeroen H.F.

AU - Hoenderop, Joost G.J.

PY - 2024/3/22

Y1 - 2024/3/22

N2 - Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.

AB - Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.

KW - CNNM2

KW - Genetic hypomagnesaemia

KW - Intellectual disability

KW - Variant characterisation

UR - http://www.scopus.com/inward/record.url?scp=85188415712&partnerID=8YFLogxK

U2 - 10.1038/s41598-024-57061-7

DO - 10.1038/s41598-024-57061-7

M3 - Article

C2 - 38519529

AN - SCOPUS:85188415712

SN - 2045-2322

VL - 14

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 6917

ER -

Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this