CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations

Accogli, Andrea; Scala, Marcello; Calcagno, Annalisa; Napoli, Flavia; Iorgi, Natascia Di; Arrigo, Serena; Mancardi, Maria Margherita; Prato, Giulia; Pisciotta, Livia; Nagel, Mato; Severino, Mariasavina; Capra, Valeria

doi:10.1016/j.ejmg.2018.07.014

Cited by 29 publications

(41 citation statements)

References 27 publications

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“…In accordance with previous studies of the CNNM2 gene [8,17,18], we found variants in the three CNNM2 regions; the extracellular domain, the transmembrane domain and the cytosolic domain. So far, only 6 pathogenic variants in the CNNM2 gene have been reported.…”

Section: Discussionsupporting

confidence: 92%

“…However, we hypothesize that variant p.(Asp335Asn) could have an effect on magnesium homeostasis. He presented with a similar phenotype than another patient previously described with hypocalciuria, elevated serum PTH levels and hypovitaminosis D, and normal serum calcium levels as well [18]. On the other hand, this other patient with a similar phenotype presented with hypomagnesemia.…”

Section: Plos Onesupporting

confidence: 56%

“…The loss of this domain presumably results in a non-functional protein impairing Mg2 + reabsorption in the kidney. It has been described that homozygous mutations in the CNNM2 gene cause hypomagnesemia, epileptic encephalopathy, brain malformations and mental retardation [18]. Nevertheless, a mild degree of intellectual disability has been described in other patients with variants in the CNNM2 gene in the heterozygous state when these variants affect important protein domains [17].…”

Section: Plos Onementioning

confidence: 99%

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Novel variant in the CNNM2 gene associated with dominant hypomagnesemia

et al. 2020

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The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p. (Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Plos Onesupporting

confidence: 56%

Section: Plos Onementioning

confidence: 99%

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Novel variant in the CNNM2 gene associated with dominant hypomagnesemia

et al. 2020

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“…For example, mutations in CNNM2 or CNNM4 cause recessively inherited dominant hypomagnesemia and renal Mg 2+ wasting [2] or Jalili Syndrome, respectively [17][18][19][20][21][22][23]. Other disorders related to their altered activity include infertility [24,25], impaired brain development [26] along with neuropsychiatric disorders [27][28][29][30], and abnormal blood pressure levels [31]. On the other hand, CNNM3 and CNNM4 are involved in cancer progression [15,32] by associating with the highly oncogenic phosphatases of the regenerating liver (PRLs) and by promoting intracellular Mg 2+ accumulation that favors tumor growth and metastasis [6,[32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Giménez-Mascarell

Oyenarte

González‐Recio

et al. 2019

IJMS

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The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.

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“…Lethality in Drosophila could therefore arise from an inability to absorb sufficient Mg 2+ through the larval gut. However, neuronally-restricted expression of uex RNAi also results in larval lethality, suggesting UEX has an additional role in early development of the nervous system, like CNNM2 in humans and zebrafish (Arjona et al, 2014;Accogli et al, 2019). Perhaps surprisingly, flies carrying homozygous or trans-heterozygous combinations of several hypomorphic uex alleles have defective appetitive and aversive memory performance, yet they seem otherwise unaffected.…”

Section: Discussionmentioning

confidence: 99%

Magnesium efflux from Drosophila Kenyon cells is critical for normal and diet-enhanced long-term memory

Funato

Meschi

et al. 2020

eLife

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Dietary magnesium (Mg2+) supplementation can enhance memory in young and aged rats. Memory-enhancing capacity was largely ascribed to increases in hippocampal synaptic density and elevated expression of the NR2B subunit of the NMDA-type glutamate receptor. Here we show that Mg2+ feeding also enhances long-term memory in Drosophila. Normal and Mg2+ enhanced fly memory appears independent of NMDA receptors in the mushroom body and instead requires expression of a conserved CNNM-type Mg2+-efflux transporter encoded by the unextended (uex) gene. UEX contains a putative cyclic nucleotide-binding homology domain and its mutation separates a vital role for uex from a function in memory. Moreover, UEX localization in mushroom body Kenyon Cells is altered in memory defective flies harboring mutations in cAMP-related genes. Functional imaging suggests that UEX-dependent efflux is required for slow rhythmic maintenance of Kenyon Cell Mg2+. We propose that regulated neuronal Mg2+ efflux is critical for normal and Mg2+ enhanced memory.

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CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations

Cited by 29 publications

References 27 publications

Novel variant in the CNNM2 gene associated with dominant hypomagnesemia

Novel variant in the CNNM2 gene associated with dominant hypomagnesemia

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Magnesium efflux from Drosophila Kenyon cells is critical for normal and diet-enhanced long-term memory

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