Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

Li, Xiucui; Bao, Shi-Jia; Wang, Wei; Shi, Xulai; Hu, Ying; Li, Feng; Zhao, Qianlei; Zheng, Fang; Lin, Zhongdong

doi:10.3389/fgene.2021.705734

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…Together with the finding that CNNM2 +/À knockout mice showed mild hypomagnesemia and developmental defects [38], all these mutations likely alter CNNM2 normal function in Mg 2+ uptake and brain development. Mutations in CNNM2 have also been observed in patients suffering from mild intellectual disability and refractory epilepsy, but without hypomagnesemia symptoms [39,40] (Table 1). Interestingly, these mutations (S743F and R746Q) reside in the cytosolic CNBH domain, which may not participate directly in Mg 2+ transport, but more in a regulatory function.…”

Section: Hypomagnesemiamentioning

confidence: 99%

New insights into the structure and function of CNNM proteins

Chen

Gehring

2023

The FEBS Journal

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Magnesium (Mg2+) is the most abundant divalent cation in cells and plays key roles in almost all biological processes. CBS‐pair domain divalent metal cation transport mediators (CNNMs) are a newly characterized class of Mg2+ transporters present throughout biology. Originally discovered in bacteria, there are four CNNM proteins in humans, which are involved in divalent cation transport, genetic diseases, and cancer. Eukaryotic CNNMs are composed of four domains: an extracellular domain, a transmembrane domain, a cystathionine‐β‐synthase (CBS)‐pair domain, and a cyclic nucleotide‐binding homology domain. The transmembrane and CBS‐pair core are the defining features of CNNM proteins with over 20 000 protein sequences known from over 8000 species. Here, we review the structural and functional studies of eukaryotic and prokaryotic CNNMs that underlie our understanding of their regulation and mechanism of ion transport. Recent structures of prokaryotic CNNMs confirm the transmembrane domain mediates ion transport with the CBS‐pair domain likely playing a regulatory role through binding divalent cations. Studies of mammalian CNNMs have identified new binding partners. These advances are driving progress in understanding this deeply conserved and widespread family of ion transporters.

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Section: Hypomagnesemiamentioning

confidence: 99%

New insights into the structure and function of CNNM proteins

Chen

Gehring

2023

The FEBS Journal

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“…The overexpression of CTNND1 has been linked to improved memory and reduced anxiety in mice 45 . The CNNM2 gene, encoding a cyclin protein involved in Mg 2+ transport, has been associated with impaired neuronal development and epilepsy 46 . RAB27B has been identified as a PTSD and depression risk locus in transcriptomic and proteomic analyses in the brain and blood 47 .…”

Section: Discussionmentioning

confidence: 99%

Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants

Friligkou,

Løkhammer,

Cabrera-Mendoza

et al. 2024

Preprint

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We leveraged information from more than 1.2 million participants to investigate the genetics of anxiety disorders across five continental ancestral groups. Ancestry-specific and cross-ancestry genome-wide association studies identified 51 anxiety-associated loci, 39 of which are novel. Additionally, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, Admixed-American, and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, the cerebral cortex, the cerebellum, the metencephalon, the entorhinal cortex, and the brain stem. Transcriptome- and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. We also observed global and local genetic correlations with depression, schizophrenia, and bipolar disorder and putative causal relationships with several physical health conditions. Overall, this study expands the knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

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“…The gene is not an intended anti-epileptic drug target, but cases have been reported with mutations in CNNM2 and epileptic seizures, both with and without hypomagnesia. 32,[38][39][40] Further, cardiovascular effects, in particular low blood pressure, are known side-effects of phenytoin, the drug linked most strongly to CNNM2. 41 These findings support a link between CNNM2 and off-target effects of antiepileptic drugs.…”

Section: Discussionmentioning

confidence: 99%

Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study

Bakker

Straten

Chong

et al. 2023

Stroke

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BACKGROUND: In a genome-wide association study of intracranial aneurysms (IA), enrichment was found between genes associated with IA and genes encoding targets of effective anti-epileptic drugs. Our aim was to assess if this pleiotropy is driven by shared disease mechanisms that could potentially highlight a treatment strategy for IA. METHODS: Using 2-sample inverse-variance weighted Mendelian randomization and genetic colocalization analyses we assessed: (1) if epilepsy liability in general affects IA risk, and (2) whether changes in gene- and protein-expression levels of anti-epileptic drug targets in blood and arterial tissue may causally affect IA risk. RESULTS: We found no overall effect of epilepsy liability on IA. Expression of 21 genes and 13 proteins corresponding to anti-epileptic drug targets supported a causal effect ( P <0.05) on IA risk. Of those genes and proteins, genetic variants affecting CNNM2 levels showed strong evidence for colocalization with IA risk (posterior probability>70%). Higher CNNM2 levels in arterial tissue were associated with increased IA risk (odds ratio, 3.02; [95% CI, 2.32–3.94]; P =3.39×10 − 16 ). CNNM2 expression was best proxied by rs11191580. The magnitude of the effect of this variant was greater than would be expected if systemic blood pressure was the sole IA-causing mechanism in this locus. CONCLUSIONS: CNNM2 is a driver of the pleiotropy between IA and anti-epileptic drug targets. Administration of the anti-epileptic drugs phenytoin, valproic acid, or carbamazepine may be expected to decrease CNNM2 levels and therefore subsequently decrease IA risk. CNNM2 is therefore an important target to investigate further for its role in the pathogenesis of IA.

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Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

Cited by 8 publications

References 20 publications

New insights into the structure and function of CNNM proteins

New insights into the structure and function of CNNM proteins

Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants

Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study

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