Chronic magnesium deficiency causes reversible mitochondrial permeability transition pore opening and impairs hypoxia tolerance in the rat heart.

Chronic magnesium (Mg) deficiency induces and exacerbates various cardiovascular diseases. We previously investigated the mechanisms underlying decline in cardiac function caused by chronic Mg deficiency and the effectiveness of Mg supplementation on this decline using the Langendorff-perfused isolated mouse heart model. Herein, we used the Langendorff-perfused isolated rat heart model to demonstrate the chronic Mg-deficient rats (Mg-deficient group) had lower the heart rate (HR) and left ventricular pressure (LVDP) than rats with normal Mg levels (normal group). Furthermore, decline in cardiac function due to hypoxia/reoxygenation injury was significantly greater in the Mg-deficient group than in the normal group. Experiments on mitochondrial permeability transition pore (mPTP) using isolated mitochondria revealed that mitochondrial membrane was fragile in the Mg-deficient group, implying that cardiac function decline through hypoxia/reoxygenation injury is associated with mitochondrial function. Mg supplementation for chronic Mg-deficient rats not only improved hypomagnesemia but also almost completely restored cardiac and mitochondrial functions. Therefore, proactive Mg supplementation in pathological conditions induced by Mg deficiency or for those at risk of developing hypomagnesemia may suppress the development and exacerbation of certain disease states.

Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects.

Patients with mutations in Cyclin M2 (CNNM2) suffer from hypomagnesaemia, seizures, and intellectual disability. Although the molecular function of CNNM2 is under debate, the protein is considered essential for renal Mg2+ reabsorption. Here, we used a Cnnm2 knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg2+ homeostasis. Breeding Cnnm2+/- mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four Cnnm2-/- pups were born alive. The Cnnm2-/- pups had a significantly lower serum Mg2+ concentration compared to wildtype littermates. Subsequently, adult Cnnm2+/- mice were fed with low, control, or high Mg2+ diets for two weeks. Adult Cnnm2+/- mice showed mild hypomagnesaemia compared to Cnnm2+/+ mice and increased serum Ca2+ levels, independent of dietary Mg2+ intake. Faecal analysis displayed increased Mg2+ and Ca2+ excretion in the Cnnm2+/- mice. Transcriptional profiling of Trpm6, Trpm7, and Slc41a1 in kidneys and colon did not reveal effects based on genotype. Microcomputed tomography analysis of the femurs demonstrated equal bone morphology and density. In conclusion, CNNM2 is vital for embryonic development and Mg2+ homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg2+ deficiency in mice and patients.

Hypomagnesemia and survival in patients with head and neck cancers who received primary concurrent chemoradiation.

BACKGROUND: Prior research has confirmed that persistent hypomagnesemia was predictive of shorter survival among patients with ovarian cancer who received carboplatin-based chemotherapy. In the current retrospective study, the authors examined the association between hypomagnesemia and survival in patients with head and neck cancer who received concurrent chemoradiation with weekly infusions of cisplatin and/or carboplatin. METHODS: Patients with head and neck cancers who had undergone chemoradiation with cisplatin and/or carboplatin between January 1, 2010, and December 31, 2014, were included. Patients were aged ≥18 years with pathology of squamous cell carcinoma of the larynx, oral cavity, or oropharynx who had received at least 30 fractions of radiotherapy with concurrent weekly cisplatin and/or carboplatin. Pathology features, laboratory results, Eastern Cooperative Oncology Group performance status, social histories, and survival were recorded. The association between hypomagnesemia and survival was analyzed controlling for known prognostic factors. RESULTS: The final cohort consisted of 439 patients with a median age of 59 years. A greater frequency of hypomagnesemia during the treatment course was found to be significantly associated with shorter survival (hazard ratio [HR], 1.13; P = .033) independent of age (HR, 1.65; P = .042), cancer site (nonoropharynx vs oropharynx: HR, 2.15 [P = .003]), Eastern Cooperative Oncology Group performance status (>1 vs ≤1: HR, 2.64 [P < .001]), and smoking history (smoker vs nonsmoker: HR, 1.88 [P = .012]). In addition, more severe hypomagnesemia was associated with shorter survival compared with the milder form. CONCLUSIONS: The frequency and severity of hypomagnesemia during treatment are prognostic of survival for patients with head and neck cancers who are receiving concurrent chemoradiation with cisplatin and/or carboplatin. A prospective study is needed to investigate the impact of the prevention of hypomagnesemia on survival in this patient population.

Influences of Hypomagnesemia on Optic Nerve and Retinal Vascular Structure Determined Using Optical Coherence Tomography (OCT) Angiography.

Purpose: To evaluate the effects of low blood magnesium levels on the optic nerve, retina, and retinal vascular structure.Methods: This observational and cross-sectional study was conducted between June 2019 and May 2020 with participants aged 20-39 years, who had a visual acuity of ≥20/20, the axial length of 22-24.5 mm, refractive defect spherical equivalent of ≤±3D, and intraocular pressure of ≤21 mm Hg. All participants had a complaint of twitching in their eyes. The participants with normal serum magnesium levels constituted the control group, and patients with hypomagnesemia constituted the patient group. Updated AngioScan software (Navis ver. 1.8.0.) of Nidek's RS-3000 Advance system was used to analyze the spectral domain-optical coherence tomography (SD-OCT) and optical coherence tomography-angiography (OCT-A) images.Results: A total of 100 right eyes of 100 individuals was included in the study. The mean retinal nerve fiber layer (RNFL) thickness was 108.52 ± 12.46 µm in the control group, and 97.3 ± 9.7 µm in the hypomagnesemia group (P < .001). In the control group, the global superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel densities (VDs) were 41.92 ± 2.29, and 37.54 ± 3.83, respectively. In the patient group, the global SCP and DCP VDs were 37.66 ± 3.14, and 32.95 ± 5.57, respectively. The SCP and DCP VD percentages were significantly lower in the patient group. The mean foveal avascular zone (FAZ) area, perimeter and circularity index (CI) were 0.32 ± 0.13 mm2, 2.89 ± 0.59 mm, and 0.52 ± 0.09, respectively, for the control group and 0.38 ± 0.11 mm2, 2.99 ± 0.64 mm, and 0.38 ± 0.1, respectively, for the patient group. The FAZ area and perimeter were significantly higher (P = .013 and P = .001) and FAZ CI was significantly lower (P < .001) in the patients with hypomagnesemia.Conclusion: Our study revealed that OCT and OCT-A measurements may be used in the determination of the optic nerve and retinal vascular structure changes in hypomagnesemia.

[Pathogenetic aspects of magnesium deficiency in connective tissue dysplasia syndrome].

The problem of connective tissue dysplasia is currently becoming particularly relevant because of significant increase of individuals with characteristic abnormalities in the structure of connective tissue. The lack of some micronutrients, arising during ontogenesis in the organism, can determine a high risk of worsening connective tissue homeostasis. Recently, the decisive role of magnesium deficiency in the progression of this disease has been demonstrated. The aim of the study was to substantiate the need for magnesium diet therapy in individuals with connective tissue dysplasia basing on the study of the pathogenetic significance of magnesium deficiency in this pathology. Material and methods. The electronic resources of the portals PubMed-NCBI, MEDLINE, the Scientific Electronic Library eLIBRARY.RU, CyberLeninka and the Google Academy were used. Results and discussion. The analysis of the obtained data made it possible to identify fundamentally new provisions on the main mechanisms of the magnesium influence on the metabolic state of all components of connective tissue. It was proved that magnesium deficiency is a predictor of worsening connective tissue homeostasis, increasing in the number of dysplastic symptoms and their severity. This pathogenetically justifies prescribing a balanced diet to patients with connective tissue dysplasia, including products rich in magnesium, taking into account its recommended daily intake, depending on age of patients. Conclusion. Adequate daily intake of magnesium will increase the mechanical properties and functionality of the connective tissue, and should be recommended for patients with connective tissue dysplasia to prevent the development of complications, maintain the quality of life and improve the prognosis for this disease.

Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubulopathy characterized by excessive urinary wasting of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure in childhood or adolescence. FHHNC is caused by mutations in CLDN16 and CLDN19, which encode the tight-junction proteins claudin-16 and claudin-19, respectively. Most of these mutations are missense mutations and large deletions are rare. METHODS: We examined the clinical and biochemical features of a Spanish boy with early onset of FHHNC symptoms. Exons and flanking intronic segments of CLDN16 and CLDN19 were analyzed by direct sequencing. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) to investigate large CLDN16 deletions. RESULTS: Genetic analysis revealed two novel compound heterozygous mutations of CLDN16, comprising a missense mutation, c.277G>A; p.(Ala93Thr), in one allele, and a gross deletion that lacked exons 4 and 5,c.(840+25_?)del, in the other allele. The patient inherited these variants from his mother and father, respectively. CONCLUSIONS: Using direct sequencing and our QMPSF assay, we identified the genetic cause of FHHNC in our patient. This QMPSF assay should facilitate the genetic diagnosis of FHHNC. Our study provided additional data on the genotypic spectrum of the CLDN16 gene.

Magnesium: The overlooked electrolyte in blood cancers?

Magnesium is an important element that has essential roles in the regulation of cell growth, division, and differentiation. Mounting evidence in the literature suggests an association between hypomagnesemia and all-cause mortality. In addition, epidemiologic studies have demonstrated that a diet poor in magnesium increases the risk of developing cancer, highlighting its importance in the field of hematology and oncology. In solid malignancies, hypomagnesemia at diagnosis portends a worse prognosis. However, little is known about prognosis in patients with hypomagnesemia and blood cancers in general; lymphoma more specifically. Hypomagnesemia has been associated with a higher viral load of the Epstein Barr virus, a virus associated with a multitude of hematologic malignancies. The role of magnesium in the immune system has been further elucidated in studies of patients with a rare primary immunodeficiency known as XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus (EBV) infection, and Neoplasia disease). These patients have a mutation in the MAGT1 gene, which codes for a magnesium transporter. The mutation leads to impaired T cell activation and an increased risk of developing hematologic malignancies. In this review we discuss the relevance of magnesium as an electrolyte, current measurement techniques, and the known data related to cause and prognosis of blood cancers. The goal is to use these data to stimulate additional high-quality and well powered studies to further investigate the role of magnesium in preventing cancer and improving outcomes of patients with malignancy and concomitant magnesium deficiency.

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Effects of Magnesium Deficiency on Mechanisms of Insulin Resistance in Type 2 Diabetes: Focusing on the Processes of Insulin Secretion and Signaling.

Magnesium (Mg2+) is an essential mineral for human health and plays an important role in the regulation of glucose homeostasis and insulin actions. Despite the widespread clinical evidences for the association of Mg2+ deficiency (MgD) and type 2 diabetes mellitus (T2D), molecular mechanisms by which Mg2+ contributes to insulin resistance (IR) are still under discussion. Mg2+ regulates electrical activity and insulin secretion in pancreatic beta-cells. Intracellular Mg2+ concentrations are critical for the phosphorylation of the insulin receptor and other downstream signal kinases of the target cells. Low Mg2+ levels result in a defective tyrosine kinase activity, post-receptor impairment in insulin action, altered cellular glucose transport, and decreased cellular glucose utilization, which promotes peripheral IR in T2D. MgD triggers chronic systemic inflammation that also potentiates IR. People with T2D may end up in a vicious circle in which MgD increases IR and IR causes MgD, that requires periodic monitoring of serum Mg2+ levels.

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

Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations.

Dietary Magnesium Alleviates Experimental Murine Colitis Through Upregulation of the Transient Receptor Potential Melastatin 6 Channel.

Background: Magnesium (Mg) is essential for human health and is absorbed mainly in the intestine. In view of the likely occurrence of an Mg deficit in inflammatory bowel disease (IBD) and the documented role of Mg in modulating inflammation, the present study addresses whether Mg availability can affect the onset and progression of intestinal inflammation. Methods: To study the correlation between Mg status and disease activity, we measured magnesemia by atomic absorption spectroscopy in a cohort of IBD patients. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, fecal occult blood, diarrhea, colon length, and histology. Expression of the transient receptor potential melastatin (TRPM) 6 channel was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry in murine colon tissues. The effect of Mg on epithelial barrier formation/repair was evaluated in human colon cell lines. Results: Inflammatory bowel disease patients presented with a substantial Mg deficit, and serum Mg levels were inversely correlated with disease activity. In mice, an Mg-deficient diet caused hypomagnesemia and aggravated DSS-induced colitis. Colitis severely compromised intestinal Mg2+ absorption due to mucosal damage and reduction in TRPM6 expression, but Mg supplementation resulted in better restoration of mucosal integrity and channel expression. Conclusions: Our results highlight the importance of evaluating and correcting magnesemia in IBD patients. The murine model suggests that Mg supplementation may represent a safe and cost-effective strategy to reduce inflammation and restore normal mucosal function.

PKC/CREB pathway mediates the expressions of GABAA receptor subunits in cultured hippocampal neurons after low-Mg2+ solution treatment.

OBJECTIVE: To investigate the potential effects of the PKC/CREB pathway on the expressions of GABAA receptor subunits α1, γ2, and δ in cultured hippocampal neurons using a model of epilepsy that employed conditions of low magnesium (Mg2+). METHODS: A total of 108 embryonic rats at the age of 18 embryonic days (E18)prepared from adult female SD rats were used as experimental subjects. Primary rat hippocampal cultures were prepared from the embryonic 18 days rats. The cultured hippocampal neurons were then treated with artificial cerebrospinal fluid containing low Mg2+ solutions to generate a low Mg2+ model of epilepsy. The low Mg2+ stimulation lasted for 3 h and then returned to in maintenance medium for 20 h. The changes of the GABAA receptor subunit α1, γ2, δ were observed by blocking or activating the function of the CREB. The quantification of the GABAA receptor subunit α1, γ2, δ and the CREB were determined by a qRT-PCR and a Western blot method. RESULTS: After the neurons were exposed to a low-Mg2+ solution for 3 h, GABAA receptor mRNA expression markedly increased compared to the control, and then gradually decreased. In contrast, CREB mRNA levels exhibited a dramatic down-regulation 3 h after terminating low-Mg2+ treatment, and then peaked at 9 h. Western blot analyses verified that staurosporine suppressed CREB phosphorylation (p-CREB). The mRNA expression of GABAA receptor subunit α1 increased only in the presence of staurosporine, whereas the expressions of subunits γ2 and δ significantly increased in the presence of either KG-501 or staurosporine. Furthermore, phorbol 12-myristate 13-acetate (PMA) decreased the expressions of GABAA subunits α1, γ2, and δ when administered alone. However, the administration of either KG-501 or staurosporine reversed the inhibitory effects of PMA. CONCLUSIONS: The PKC/CREB pathway may negatively regulate the expressions of GABAA receptor subunits α1, γ2, and δ in cultured hippocampal neurons in low Mg2+ model of epilepsy.

Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions.

The bone is the main storage site for Ca2+ and Mg2+ ions in the mammalian body. Although investigations into Ca2+ signaling have progressed rapidly and led to better understanding of bone biology, the Mg2+ signaling pathway and associated molecules remain to be elucidated. Here, we investigated the role of a potential Mg2+ signaling-related lysosomal molecule, two-pore channel subtype 2 (TPC2), in osteoclast differentiation and bone remodeling. Previously, we found that under normal Mg2+ conditions, TPC2 promotes osteoclastogenesis. We observed that under low-Mg2+ conditions, TPC2 inhibited, rather than promoted, the osteoclast differentiation and that the phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) signaling pathway played a role in the TPC2 activation under low-Mg2+ conditions. Furthermore, PI(3,5)P2 depolarized the membrane potential by increasing the intracellular Na+ levels. To investigate how membrane depolarization affects osteoclast differentiation, we generated a light-sensitive cell line and developed a system for the light-stimulated depolarization of the membrane potential. The light-induced depolarization inhibited the osteoclast differentiation. We then tested the effect of myo-inositol supplementation, which increased the PI(3,5)P2 levels in mice fed a low-Mg2+ diet. The myo-inositol supplementation rescued the low-Mg2+ diet-induced trabecular bone loss, which was accompanied by the inhibition of osteoclastogenesis. These results indicate that low-Mg2+-induced osteoclastogenesis involves changes in the role of TPC2, which are mediated through the PI(3,5)P2 pathway. Our findings also suggest that myo-inositol consumption might provide beneficial effects in Mg2+ deficiency-induced skeletal diseases.

Substrain and light regime effects on integrated anxiety-related behavioral z-scores in male C57BL/6 mice-Hypomagnesaemia has only a small effect on avoidance behavior.

Magnesium (Mg) has been described to possess an anxiolytic function, but a number of studies present inconsistent results on this matter. In this study the effect of Mg deficiency on anxiety-related behavior, brain and blood plasma Mg in young adult male C57BL/6JOlaHsd and C57BL/6NCrl mice was studied. The animals were put on a control or Mg deficient diet from day 0 and significant hypomagnesaemia was evident from day 12 onwards in the test animals. Housing and test conditions were under either conventional light regime (white light behavioral test conditions) or reverse light regime (red light behavioral test conditions). The animals were tested in three tests for unconditioned anxiety: the modified Hole Board (day 14), the light-dark test (day 21) and the elevated plus maze (day 28). Overall integrated behavioral z-scores were calculated over these three behavioral tests. Mg showed a structure dependent distribution at the level of the brain, that differed between C57BL/6 substrain and light regime (conventional versus reverse), respectively. Likewise, total brain Mg did differ between substrain and light regime, but was not affected by the diet. Animals on the Mg deficient diet housed under conventional light regime had a higher final (day 28) blood plasma corticosterone level as compared to controls. Animals housed under reverse light regime exhibited no diet effect of plasma corticosterone levels. The significant hypomagnesaemia at blood plasma level resulted in an effect of Mg deficiency on avoidance, but not overall anxiety-related behavior. Significant differences regarding avoidance behavior were found between the two substrains and light regimes, respectively.

Ionized Magnesium and Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy.

BACKGROUND: The regional citrate anticoagulation (RCA) induces changes in total (Catot) and ionized (Ca2+) calcium. As of now, we do not have much information about parallel changes of total (Mgtot) and ionized (Mg2+) magnesium. METHODS: The authors compared changes of Mg2+ and Mgtot with changes of Ca2+ and Catot in 32 critically ill patients on 4% trisodium citrate (4% TSC) with calcium-free fluids. RESULTS: The median continuous venovenous hemodiafiltration balance of Mgtot was -0.91 (-1.18 to -0.53) mmol/h compared to the median balance of Catot 0.86 (0.08-1.55) mmol/h. Postfilter Mg2+ decreased by 68.3% (70.8-65.6) in parallel (r = 0.41, p = 0.03) to decrease of postfilter Ca2+ (by 70.2% (73.0-66.1)) and was significantly related to the postfilter Ca2+ (r = 0.50, p < 0.001). The decrease of prefilter to postfilter Ca2+ correlated to a dosage of 4% TSC per blood flow (r = 0.37, p = 0.04). CONCLUSIONS: The loss of Mgtot during RCA is not covered by magnesium concentration in ordinary dialysis/substitution fluid and may lead to the depletion of total body magnesium. The postfilter Mg2+ is significantly related to the postfilter Ca2+. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi = 440972.

Magnesium deficiency during pregnancy in mice impairs placental size and function.

OBJECTIVE: Maternal magnesium (Mg) deficiency has been associated with fetal growth restriction. Using a mouse model of maternal Mg deficiency-induced fetal growth restriction, we sought to investigate the effect of Mg deficiency on placental physiology and function. METHODS: In vivo: Pregnant Swiss Webster mice were fed either 100% of the recommended amount of Mg (control) or 10%Mg (Mg-deficient) (8 per group). Dams were euthanized on gestational day 17 and placentas were collected, weighed and assessed for Mg concentrations, as well as nutrient transporter mRNA expression. For nutrient transfer studies, control and Mg-deficient dams (6 per group) were injected with (14)C-amino acids and (3)H-glucose and trans-placental passage was determined. In vitro: BeWo placental cells were grown in media containing 10%Mg to 100%Mg and the effects of Mg status on cell proliferation, oxidative stress and nutrient uptake were measured. Data were analyzed by Student's t-tests comparing controls vs. Mg-deficient animals or cells. For multiple comparisons, data were analyzed by ANOVA followed by Dunnett's post hoc testing. RESULTS: In vivo: Maternal Mg deficiency decreased placental Mg content, placental and fetal weights, ratio of fetal:placental weight (P < 0.05), placental Slc7a5 transporter mRNA expression and transplacental nutrient transport (P < 0.05). In vitro: Mg deficiency reduced BeWo nutrient uptake (P < 0.01) and cell proliferation (P < 0.01), and increased oxidative stress (P < 0.01). CONCLUSION: These findings highlight the adverse effects of maternal Mg deficiency on fetal weight and placental function, including transport and proliferation and may explain the fetal growth restriction observed with moderate Mg deficiency in mice.

A Novel Homozygous Mutation in the Transient Receptor Potential Melastatin 6 Gene: A Case Report.

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by mutations in the transient receptor potential melastatin 6 (TRPM6) gene. Affected individuals present in early infancy with seizures caused by the severe hypocalcemia and hypomagnesemia. By presenting this case report, we also aimed to highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia. A Turkish inbred girl, now aged six years, had presented to another hospital at age two months with seizures diagnosed to be due to hypomagnesemia. She was on magnesium replacement therapy when she was admitted to our clinic with complaints of chronic diarrhea at age 3.6 years. During her follow-up in our clinic, she showed an age-appropriate physical and neurological development. In molecular genetic analysis, a novel homozygous frame-shift mutation (c.3447delT>p.F1149fs) was identified in the TRPM6 gene. This mutation leads to a truncation of the TRPM6 protein, thereby complete loss of function. We present the clinical follow-up findings of a pediatric HSH case due to a novel mutation in the TRPM6 gene and highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia.

Comparative angioprotective effects of magnesium compounds.

Magnesium (Mg) deficiency is implicated in the development of numerous disorders of the cardiovascular system. Moreover, the data regarding the efficacy of different magnesium compounds in the correction of impaired functions due to low magnesium intake are often fragmentary and inconsistent. The aim of this study was to compare the effects of the most bioavailable Mg compounds (Mg l-aspartate, Mg N-acetyltaurate, Mg chloride, Mg sulphate and Mg oxybutyrate) on systemic inflammation and endothelial dysfunction in rats fed a low Mg diet for 74 days. A low Mg diet decreased the Mg concentration in the plasma and erythrocytes, which was accompanied by a reduced concentration of eNOs and increased levels of endothelin-1 level in the serum and impaired endothelium-dependent vasodilatation. These effects increased the concentration of proinflammatory molecules, such as VCAM-1, TNF-α, IL-6 and CRP, indicating the development of systemic inflammation and endothelial dysfunction. The increased total NO level, which estimated from the sum of the nitrate and nitrite concentrations in the serum, may also be considered to be a proinflammatory marker. Two weeks of Mg supplementation partially or fully normalised the ability of the vascular wall to effect adequate endothelium-dependent vasodilatation and reversed the levels of most endothelial dysfunction and inflammatory markers (except CRP) to the mean values of the control group. Mg sulphate had the smallest effect on the endothelin-1, TNF-α and VCAM-1 levels. Mg N-acetyltaurate was significantly more effective in restoring the level of eNOS compared to all other studied compounds, except for Mg oxybutyrate. Taken together, the present findings demonstrate that all Mg compounds equally alleviate endothelial dysfunction and inflammation caused by Mg deficiency. Mg sulphate tended to be the least effective compound.

Dietary magnesium restriction reduces amygdala-hypothalamic GluN1 receptor complex levels in mice.

Reduced daily intake of magnesium (Mg(2+)) is suggested to contribute to depression. Indeed, preclinical studies show dietary magnesium restriction (MgR) elicits enhanced depression-like behaviour establishing a causal relationship. Amongst other mechanisms, Mg(2+) gates the activity of N-methyl-D-asparte (NMDA) receptors; however, it is not known whether reduced dietary Mg(2+) intake can indeed affect brain NMDA receptor complexes. Thus, the aim of the current study was to reveal whether MgR induces changes in brain NMDA receptor subunit composition that would indicate altered NMDA receptor regulation. The results revealed that enhanced depression-like behaviour elicited by MgR was associated with reduced amygdala-hypothalamic protein levels of GluN1-containing NMDA complexes. No change in GluN1 mRNA levels was observed indicating posttranslational changes were induced by dietary Mg(2+) restriction. To reveal possible protein interaction partners, GluN1 immunoprecipitation and proximity ligation assays were carried out revealing the expected GluN1 subunit association with GluN2A, GluN2B, but also novel interactions with GluA1, GluA2 in addition to known downstream signalling proteins. Chronic paroxetine treatment in MgR mice normalized enhanced depression-like behaviour, but did not alter protein levels of GluN1-containing NMDA receptors, indicating targets downstream of the NMDA receptor. Collectively, present data demonstrate that dietary MgR alters brain levels of GluN1-containing NMDA receptor complexes, containing GluN2A, GluN2B, AMPA receptors GluA1, GluA2 and several protein kinases. These data indicate that the modulation of dietary Mg(2+) intake may alter the function and signalling of this receptor complex indicating its involvement in the enhanced depression-like behaviour elicited by MgR.