Primary familial brain calcification with a novel <i>SLC20A2</i> mutation: Analysis of PiT‐2 expression and localization

Taglia, Ilaria; Formichi, Patrizia; Battisti, Carla; Peppoloni, Giulia; Barghigiani, Melissa; Tessa, Alessandra; Federico, Antonio

doi:10.1002/jcp.26104

Cited by 15 publications

(7 citation statements)

References 30 publications

(35 reference statements)

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“…3F ). Patients with primary familial brain calcification disease carry a novel duplication of 626 WFVT in h PiT, which corresponds to 378 WLLI in Tm PiT ( 28 ). This mutation does not affect expression of h PiT, but it does alter subcellular protein localization and impairs Pi internalization ( 28 ).…”

Section: Resultsmentioning

confidence: 99%

Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20

et al. 2020

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Inorganic phosphate (Pi) is a fundamental and essential element for nucleotide biosynthesis, energy supply, and cellular signaling in living organisms. Human phosphate transporter (hPiT) dysfunction causes numerous diseases, but the molecular mechanism underlying transporters remains elusive. We report the structure of the sodium-dependent phosphate transporter from Thermotoga maritima (TmPiT) in complex with sodium and phosphate (TmPiT-Na/Pi) at 2.3-angstrom resolution. We reveal that one phosphate and two sodium ions (Pi-2Na) are located at the core of TmPiT and that the third sodium ion (Nafore) is located near the inner membrane boundary. We propose an elevator-like mechanism for sodium and phosphate transport by TmPiT, with the TmPiT-Na/Pi complex adopting an inward occluded conformation. We found that disease-related hPiT variants carry mutations in the corresponding sodium- and phosphate-binding residues identified in TmPiT. Our three-dimensional structure of TmPiT provides a framework for understanding PiT dysfunction and for future structure-based drug design.

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Section: Resultsmentioning

confidence: 99%

Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20

et al. 2020

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“…Taglia et al . have shown that in PiT-2 trp626_629dup patients, PiT-2 does not migrate to the membrane and is abnormally localized to the nucleus 37 . Yamada et al .…”

Section: Discussionmentioning

confidence: 99%

Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification

Nishii

Shimogawa

Kurita

et al. 2019

Sci Rep

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Idiopathic basal ganglia calcification (IBGC) is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. SLC20A2 is encoding the phosphate transporter PiT-2 and was identified in 2012 as the causative gene of familial IBGC. In this study, we investigated functionally two novel SLC20A2 variants (c.680C > T, c.1487G > A) and two SLC20A2 variants (c.82G > A, c.358G > C) previously reported from patients with IBGC. We evaluated the function of variant PiT-2 using stable cell lines. While inorganic phosphate (Pi) transport activity was abolished in the cells with c.82G > A, c.358G > C, and c.1487G > A variants, activity was maintained at 27.8% of the reference level in cells with the c.680C > T variant. Surprisingly, the c.680C > T variant had been discovered by chance in healthy members of an IBGC family, suggesting that partial preservation of Pi transport activity may avoid the onset of IBGC. In addition, we confirmed that PiT-2 variants could be translocated into the cell membrane to the same extent as PiT-2 wild type. In conclusion, we investigated the PiT-2 dysfunction of four SLC20A2 variants and suggested that a partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of IBGC.

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“…Some of these mutations are loss‐of‐function mutations, in which improperly produced proteins are unable to act as a phosphate transporter (Hsu et al, 2013; López‐Sánchez et al, 2020). The precipitation of calcium phosphate in brain tissue that is detected in PFBC results from the accumulation of phosphate ions in the cell through the ineffective export and retention of Pi in the extracellular space (Anheim et al, 2016; Taglia et al, 2018). In the present study, we noticed a slightly different tendency.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemic environment disrupts phosphate transporter function and promotes calcification processes in podocytes and isolated glomeruli

Kulesza

Typiak

Rachubik

et al. 2022

Journal Cellular Physiology

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Soft tissue calcification is a pathological phenomenon that often occurs in end-stage chronic kidney disease (CKD), which is caused by diabetic nephropathy, among other factors. Hyperphosphatemia present during course of CKD contributes to impairments in kidney function, particularly damages in the glomerular filtration barrier (GFB). Essential elements of the GFB include glomerular epithelial cells, called podocytes. In the present study, we found that human immortalized podocytes express messenger RNA and protein of phosphate transporters, including NaPi 2c (SLC34A3), Pit 1 (SLC20A1), and Pit 2 (SLC20A2), which are sodium-dependent and mediate intracellular phosphate (Pi) transport, and XPR1, which is responsible for extracellular Pi transport. We found that cells that were grown in a medium with a high glucose (HG) concentration (30 mM) expressed less Pit 1 and Pit 2 protein than podocytes that were cultured in a standard glucose medium (11 mM). We found that exposure of the analyzed transporters in the cell membrane of the podocyte is altered by HG conditions. We also found that the activity of tissue nonspecific alkaline phosphatase increased in HG, causing a rise in Pi generation. Additionally, HG led to a reduction of the amount of ectonucleotide pyrophosphatase/phosphodiesterase 1 in the cell membrane of podocytes. The extracellular concentration of pyrophosphate also decreased under HG conditions. These data suggest that a hyperglycemic environment enhances the production of Pi in podocytes and its retention in the extracellular space, which may induce glomerular calcification.

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Primary familial brain calcification with a novel SLC20A2 mutation: Analysis of PiT‐2 expression and localization

Cited by 15 publications

References 30 publications

Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20

Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20

Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification

Hyperglycemic environment disrupts phosphate transporter function and promotes calcification processes in podocytes and isolated glomeruli

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