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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.
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Details
1 Radboudumc, Department of Medical BioSciences, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382)
2 University of the Basque Country (UPV/EHU), Biobizkaia Health Research Institute, Division of Pediatric Metabolism, Cruces University Hospital, CIBER-ER, Metab-ERN, Barakaldo, Spain (GRID:grid.411232.7) (ISNI:0000 0004 1767 5135)
3 Biocruces Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Pediatric Nephrology Department, Cruces University Hospital, CIBERDEM, CIBER-ER, Endo-ERN, Barakaldo, Spain (GRID:grid.11480.3c) (ISNI:0000000121671098)
4 Erasmus MC, Deparment of Clinical Genetics, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X); Erasmus MC, Discovery Unit, Department of Clinical Genetics, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X); Erasmus MC, ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X)
5 Erasmus MC, ENCORE Expertise Center for Neurodevelopmental Disorders, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X); Erasmus Medical Center Sophia Children’s Hospital, Department of General Pediatrics, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X)
6 Erasmus MC, Deparment of Clinical Genetics, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:0000 0004 0459 992X)
7 Hospital Universitario Nuestra Señora de Candelaria, Unidad de Investigación, Renal Tube Group, Santa Cruz de Tenerife, Spain (GRID:grid.411331.5) (ISNI:0000 0004 1771 1220)
8 University Medical Center Utrecht, Department of Genetics, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000 0000 9012 6352)
9 AP-HP, universite Paris Cité, Service de medecine genomique des maladies rares, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602); hopital Européen Georges Pompidou, Centre de reference des maladies renales hereditaires de l’enfant et de l’adulte MARHEA, Paris, France (GRID:grid.414093.b) (ISNI:0000 0001 2183 5849); Sorbonne universite, universite Paris Cité, CNRS, centre de recherche des Cordeliers, Inserm UMRS 1138, Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282)
10 Hôpital Édouard Herriot, Hospices civils de Lyon, service de nephrologie, dialyse, hypertension et exploration fonctionnelle renale, Lyon, France (GRID:grid.412180.e) (ISNI:0000 0001 2198 4166); Hôpital Femme-Mère-Enfant Bron, Centre de reference des maladies renales rares et phosphocalciques, Nephrogones, Bron, France (GRID:grid.414103.3) (ISNI:0000 0004 1798 2194); Université Claude Bernard Lyon 1, Faculté de medecine Lyon est, Villeurbanne, France (GRID:grid.7849.2) (ISNI:0000 0001 2150 7757)
11 Bizkaia Science and Technology Park, Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain (GRID:grid.420161.0)