Abstract
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.
Highlights
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
PiT-2 encoded by SLC20A2 is a sodium-dependent phosphate type III transporter belonging to the inorganic phosphate transporter (PiT) family[11]
Before the discovery of SLC20A2 variants in patients with IBGC, Bottger, P. and Pedersen, L. had shown that the artificial replacements E55K, E575K, D28N, and D506N were leading to PiT-2 variants unable to transport Pi into the plasma of Xenopus laevis oocytes[21,22]
Summary
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. 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. SLC20A2 (IBGC1 was previously named IBGC3) encoding the phosphate transporter PiT-2 was first identified in 2012 as the first causative gene of IBGC6. Before the discovery of SLC20A2 variants in patients with IBGC, Bottger, P. and Pedersen, L. had shown that the artificial replacements E55K, E575K, D28N, and D506N were leading to PiT-2 variants unable to transport Pi into the plasma of Xenopus laevis oocytes[21,22]. Wang et al showed that the six variants, S601W, S601L, T595M, E575K, G498R, and V42del, of SLC20A2 in patients with IBGC caused a Pi transport dysfunction of PiT-2 using Xenopus laevis oocytes[6]. Bottger, P. and Pedersen, L. have shown the importance of PD1131 for maintaining Pi transport activities with artificial replacement or deletion in PiT-221,22,26
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