scholarly journals Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis

2020 ◽  
Vol 295 (28) ◽  
pp. 9366-9378 ◽  
Author(s):  
Uriel López-Sánchez ◽  
Sandrine Tury ◽  
Gaël Nicolas ◽  
Miranda S. Wilson ◽  
Snejana Jurici ◽  
...  
Keyword(s):  
Phosphate Uptake ◽  
Neuropsychiatric Symptoms ◽  
Binding Pocket ◽  
Inositol Polyphosphate ◽  
Phosphate Homeostasis ◽  
Inositol Polyphosphates ◽  
Inositol Pyrophosphate ◽  
Atp Levels ◽  
Primary Familial Brain Calcification ◽  
Brain Calcification

Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters with the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis, and we identified XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of WT SLC20A2 increased phosphate uptake, as expected, but also unexpectedly increased phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1 KO cells. Elevated ATP levels are a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with WT XPR1 but not with XPR1 harboring a mutated PP-IP–binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and alteration of this interplay likely contributes to PFBC.

scholarly journals An ATP-responsive metabolic cassette comprised of inositol tris/tetrakisphosphate kinase 1 (ITPK1) and inositol pentakisphosphate 2-kinase (IPK1) buffers diphosphosphoinositol phosphate levels

2020 ◽  
Vol 477 (14) ◽  
pp. 2621-2638 ◽  
Author(s):  
Hayley Whitfield ◽  
Gaye White ◽  
Colleen Sprigg ◽  
Andrew M. Riley ◽  
Barry V.L. Potter ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Inositol Phosphate ◽  
High Energy ◽  
Dependent Manner ◽  
Inositol Polyphosphate ◽  
Inositol Polyphosphates ◽  
Inositol Pyrophosphate ◽  
Relative Contribution ◽  
Chromatographic Resolution ◽  
Molecular Signals

Inositol polyphosphates are ubiquitous molecular signals in metazoans, as are their pyrophosphorylated derivatives that bear a so-called ‘high-energy’ phosphoanhydride bond. A structural rationale is provided for the ability of Arabidopsis inositol tris/tetrakisphosphate kinase 1 to discriminate between symmetric and enantiomeric substrates in the production of diverse symmetric and asymmetric myo-inositol phosphate and diphospho-myo-inositol phosphate (inositol pyrophosphate) products. Simple tools are applied to chromatographic resolution and detection of known and novel diphosphoinositol phosphates without resort to radiolabeling approaches. It is shown that inositol tris/tetrakisphosphate kinase 1 and inositol pentakisphosphate 2-kinase comprise a reversible metabolic cassette converting Ins(3,4,5,6)P4 into 5-InsP7 and back in a nucleotide-dependent manner. Thus, inositol tris/tetrakisphosphate kinase 1 is a nexus of bioenergetics status and inositol polyphosphate/diphosphoinositol phosphate metabolism. As such, it commands a role in plants that evolution has assigned to a different class of enzyme in mammalian cells. The findings and the methods described will enable a full appraisal of the role of diphosphoinositol phosphates in plants and particularly the relative contribution of reversible inositol phosphate hydroxykinase and inositol phosphate phosphokinase activities to plant physiology.

scholarly journals Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series

Neurogenetics ◽  
2021 ◽  
Author(s):  
Luca Magistrelli ◽  
Roberta Croce ◽  
Fabiola De Marchi ◽  
Chiara Basagni ◽  
Miryam Carecchio ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Case Series ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Phenotypic Spectrum ◽  
Primary Familial Brain Calcification ◽  
Psychiatric Disturbances ◽  
Brain Calcification ◽  
Uncertain Significance ◽  
Six Genes

AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

scholarly journals Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3601
Author(s):  
Raja Mohanrao ◽  
Ruth Manorama ◽  
Shubhra Ganguli ◽  
Mithun C. Madhusudhanan ◽  
Rashna Bhandari ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Atpase Activity ◽  
Catalytic Domain ◽  
Inositol Phosphate ◽  
Substrate Recognition ◽  
Competitive Inhibitor ◽  
Inositol Polyphosphates ◽  
Inositol Pyrophosphate ◽  
Phosphate Donor ◽  
Inositol Pyrophosphates

IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates—scyllo-IP5, scyllo-IP6, scyllo-IP7 and Bz-scyllo-IP5—from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.

scholarly journals MYORG is associated with recessive primary familial brain calcification

2018 ◽  
Vol 6 (1) ◽  
pp. 106-113 ◽  
Author(s):  
David Arkadir ◽  
Alexander Lossos ◽  
Dolev Rahat ◽  
Muneer Abu Snineh ◽  
Ora Schueler-Furman ◽  
...  
Keyword(s):  
Primary Familial Brain Calcification ◽  
Brain Calcification

scholarly journals Evaluation of chronic hypoparathyroidism course according to the Database of Endocrinology Research Centre

2020 ◽  
Vol 66 (5) ◽  
pp. 7-14
Author(s):  
E. V. Kovaleva ◽  
A. R. Ajnetdinova ◽  
A. K. Eremkina ◽  
N. G. Mokrysheva
Keyword(s):  
Conventional Therapy ◽  
Neuropsychiatric Symptoms ◽  
Visual Disturbance ◽  
Research Centre ◽  
Cross Sectional ◽  
Large Databases ◽  
Brain Calcification ◽  
Quality Of Medical Care ◽  
Chronic Hypoparathyroidism

BACKGRAUND: Currently high frequency of thyroid or parathyroid surgery is associated with significant increased incidence of hypoparathyroidism. Evaluation of the epidemiological and clinical features of chronic hypoparathyroidism is necessary to predict social-significant complications and to improve the quality of medical care.AIMS: To estimate clinical and demographic features, different regimens and efficacy of conventional therapy in patients with chronic postsurgical and nonsurgical hypoparathyroidism.MATERIALS AND METHODS: The cross-sectional, observational, continuous study was carried out based on Database of patients with chronic postsurgical and nonsurgical hypoparathyroidism of Endocrinology Research Centre, Moscow. 293 patients from 61 regions of the Russian Federation were included in this study. Statistical analysis was done on June 2020. The descriptive statistics are presented by medians (Ме) and the first and third quartiles (Q1; Q3) and by absolute and relative frequencies.RESULTS: Hypoparathyroidism was most often recorded in women (85%) at the age of 43 [32; 52] years, after thyroid surgery. Less than a half of the study group had target indicators of serum calcium and phosphate levels (31% and 47%, respectively) despite ongoing treatment. A complex instrumental examination for the disease complications was performed in 58% of cases (n = 169). Among them, kidney disorders were detected in 38%, visual disturbance in 14%, brain calcification in 10%, arrhythmias in 4% and neuropsychiatric symptoms in 6%. Conventional therapy with calcium supplements and activated vitamin D analogues was noted in 75% of patients.CONCLUSIONS: The analysis of large databases of patients with chronic hypoparathyroidism is a necessary tool for determining of optimal clinical and therapeutic approaches, as well as prognostic markers of disease complications.

scholarly journals Vascular calcification has a role in acute non-renal phosphate clearance

2020 ◽  
Author(s):  
Mandy E Turner ◽  
Austin P Lansing ◽  
Paul S Jeronimo ◽  
Lok Hang Lee ◽  
Bruno A Svajger ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Phosphate Uptake ◽  
Mineral Metabolism ◽  
Extracellular Fluid ◽  
Systemic Response ◽  
Phosphate Homeostasis ◽  
Rat Models ◽  
Oral Consumption ◽  
Circulating Levels ◽  
Systemic Disposition

AbstractRationaleNon-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is especially relevant in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC).ObjectiveDetermine whether the systemic response to acute phosphate challenges is altered by the development and progression of VC.Methods/ResultsAcute circulating and tissue deposition of an acute phosphate challenge was assessed in two rat models of VC using radio-labelled phosphate tracer. In an adenine-induced model of CKD with VC, animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition could be traced to the calcifying vasculature. In a non-CKD model of VC, VC was induced with 0.5ug/kg calcitriol and then withdrawn. The radio-labelled phosphate challenge was given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. The new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate.ConclusionsOur data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

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