TY - JOUR
T1 - Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification
AU - Nishii, Kazuya
AU - Shimogawa, Ritsuko
AU - Kurita, Hisaka
AU - Inden, Masatoshi
AU - Kobayashi, Michio
AU - Toyoshima, Itaru
AU - Taguchi, Yoshiharu
AU - Ueda, Akihiro
AU - Tamune, Hidetaka
AU - Hozumi, Isao
N1 - Funding Information:
Subjects and samples. We collected clinical information on patients with IBGC in a nationwide study supported by a grant for research on intractable diseases from the Ministry of Health, Labor and Welfare of Japan. The diagnostic criteria were described previously4. Briefly, patients with causative biochemical abnormalities, including calcium, inorganic phosphate, and intact parathyroid hormone (iPTH), were excluded. The genetic survey and all experiments on human blood samples were approved by the Ethics Committees of Gifu University and Gifu Pharmaceutical University and performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan, and Ethical Guidelines for Human Genome/Gene Analysis Research in Japan. After written informed consent was obtained, peripheral blood samples were collected. This study was registered to the UMIN Clinical Trials Registry approved by International Committee of Medical Journal Editors (UMIN000030100).
Funding Information:
This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan (H26-Nanbyotou (Nan)-Ippan-001, H26-Nanchitoh (Nan)-Ippan-085), the Ministry of Education, Culture, Sports, Science and Technology of Japan (Basic Research (B) (17H04198) and the Japan Agency for Medical Research and Development (AMED) (18ek0109313h0001 and 18ek0109372h0001) in Japan.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41598-019-53401-0
DO - 10.1038/s41598-019-53401-0
M3 - Article
C2 - 31754123
AN - SCOPUS:85075456660
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 17288
ER -