ORIGINAL RESEARCH article
Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1600877
This article is part of the Research TopicOmic Technologies, Integrative Methods and Translational Approaches in Brain Health and DiseaseView all articles
Two novel variants in CNNM2 disrupts magnesium efflux leading to neurodevelopmental disorders
Provisionally accepted- 1Central South University, Changsha, China
- 2Changsha Hospital for Maternal and Child Health Care, Changsha, Hunan Province, China
- 3Hunan Jiahui Genetics Hospital, Central South University, Changsha, China
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Background: Hypomagnesemia, seizures, and impaired intellectual development 1 (HOMGSMR1) is a rare neurodevelopmental disorder associated with magnesium homeostasis disruption, caused by mutations in the CNNM2 gene. HOMGSMR1 demonstrates considerable clinical heterogeneity, but the genotype-phenotype relationship remains insufficient. Methods: We recruited two unrelated families with NDDs, and potential variants were identified through whole exome sequencing and confirmed by Sanger sequencing. Quantitative PCR, western blotting, immunofluorescent staining, and flow cytometry were used to assess functional changes in candidate CNNM2 variants. Results: Two novel variants, p.E298del and p.P360R, in CNNM2 gene were identified. The unique facial features of proband 1 may broaden the known phenotypic spectrum of HOMGSMR1. Functional studies confirmed that the p.E298del and p.P360R variants increased CNNM2 transcription and protein levels, impairing the proper localization of the CNNM2 protein to the cell membrane. Two variant proteins accumulated in the cytoplasm and formed clumps. Furthermore, intracellular Mg²⁺ levels were higher in cells with these variants, disrupting magnesium homeostasis and potentially contributing to hypomagnesemia. Notably, the proteins of these two variants exhibited reduced stability and were prone to degradation, potentially providing new insights into the pathogenic mechanisms of CNNM2. Conclusion: Our study expands the mutation and phenotypic spectrum, as well as the functional studies of CNNM2, and contributes to genetic testing and prenatal diagnosis in families with HOMGSMR1.
Keywords: hypomagnesemia, Seizures, Intellectual Disability, whole exome sequencing, CNNM2
Received: 27 Mar 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Li, Liu, Liu, Liu, Lu, Wen, Zhu, Liang, Li and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhuo Li, Central South University, Changsha, China
Lingqian Wu, Central South University, Changsha, China
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