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

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.

SLC20A2-Associated Idiopathic Basal Ganglia Calcification-Related Recurrent Psychosis Response to Low-Dose Antipsychotics: A Case Report and Literature Review

“…Genetic analysis revealed a heterozygous SLC20A2 missense mutation (c.1487G > A, p.C496Y in exon 8) located at chromosome 8p11.21, which we published with its functional assessment elsewhere [8], confirming the clinical diagnosis of IBGC. The patient was discharged from the hospital within one month.…”

“…Pathophysiologically, SLC20A2 gene encodes PiT-2, which is a type III Na-dependent Pi transporter. Pi level is reported to be elevated in the cerebrospinal fluid of patients with IBGC [8]. Further, it is postulated that the cell calcification mechanism involves the complex formation between extracellular Pi (high concentrations) and Ca 2+ and other metal ions, which causes Ca 2+ ions to flow into cells and promote bone differentiation; however, no relationship between the gene mutation site and degree of calcification or clinical phenotype has been established, partly because of insufficient information on the phenotype [1,9].…”

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

“…Slc20a2-HE mice, maintained in very few laboratories, with approximately 25% Slc20a2 expression relative to that in WT mice, also simulate brain calcification phenotype in patients with PFBC (Wallingford et al, 2017). In patients with PFBC, SLC20A2 gene dosage roughly correlates with the brain total calcification score (Wang et al, 2012;Chen et al, 2019) and partially reduces the Pi transport function of PIT-2 which might be insufficient to induce brain calcification (Nishii et al, 2019). Calcification degree and scope could be revealed by CT scan in the clinic, and these brain lesions had nearly complete penetrance for those harboring causative mutations, whereas its variable expressivity among patients with PFBC suggests the detrimental or protective effects of other genetic modifiers.…”

The Genetics of Primary Familial Brain Calcification: A Literature Review

“…SLC20A2 is the most common PFBC gene; heterozygous variants have been identified in more than 60% of genetically confirmed PFBC patients [ 3 ]. A missense change is the most common variant type, followed by frameshift, nonsense, and splice site variations, without obvious hotspots for pathogenic variants ( Figure 1 a) [ 3 , 6 , 7 , 17 , 18 , 21 , 23 , 37 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. Functionally, both haploinsufficiency and dominant negative effects have been described; the loss of normal PiT2 function results in extracellular Pi accumulation and subsequent calcium phosphate formation [ 6 , 42 ].…”