Familial IBGC, also known as Fahr disease, is a rare disorder. Its major clinical features include symmetrical bilateral calcification of the basal ganglia in the absence of any abnormal serum levels of calcium or phosphorus 
. The patients may show different symptoms, including cognitive impairment, schizophrenia, parkinsonism, and cerebellar ataxia, ranging in severity from undetectable to severe 
Dai et al. mapped an IBGC locus to chromosome 8p21.1-q11.23 in a study performed on a large Chinese family 
. Recently, Dai's research group sequenced candidate genes in this locus and identified several mutations in SLC20A2
Pi transport assays in Xenopus laevis
oocytes showed that the mutations resulted in significant impairment of Pi transport. In the present study, we screened for the SLC20A2
mutations in the PJ-IBGC family, and identified a novel heterozygous single base-pair deletion, c.510delA (p.R172fsX19), in SLC20A2
exon 4. The mutation is predicted to result in a frameshift, producing a truncated SLC protein with a premature termination codon, which most likely leads to a complete loss of function in SLC20A2
. Compared with the work of Wang et al. 
, we performed further confirmation by directly examining the SLC20A2
mRNA expression in cells from affected individuals and showed a 30% reduction. Our research indicates that insufficient expression of SLC20A2
is the molecular basis for FIBGC.
Pi is indispensable for all life processes, and Pi homeostasis is precisely controlled at several levels by sodium/phosphate co-transporters. Type-2 sodium/phosphate co-transporters (SLC34) are strongly expressed in the kidneys and intestinal mucosa; they are involved in the absorption of Pi from the intestine and the recycling of Pi from the kidneys 
. SLC20A2, also known as pit2, is a type III Na-Pi co-transporter. The type III Na-Pi co-transporters are expressed in all investigated tissues and cells of the human body 
. Both SLC20A1 and SLC20A2 have been used by viruses as receptors for cell invasion 
. The widespread expression of SLC20A1 and SLC20A2 indicates that they may play a key role in the regulation of Pi homeostasis at the micro-environmental level, and regional differential expression of these two proteins may lead to a different local level of Pi. This may affect Pi-related physical processes, including calcification.
Although a mutation in SLC20A2
was identified as the genetic basis for the IBGC, several questions still need to be answered: 1. If all of the cells within the body have the same mutation, why does the calcification only occur within the brain? 2. Why does the calcification usually begin in the globus pallidus? 3. Is the location of the calcification consistent with expression of SLC20A2? The expression of SLC20A2 within mouse and human brains was investigated (Allen Brain Atlas, http://human.brain-map.org
). The results show that the expression of SLC20A2 was high in regions that usually show calcification in IBGC patients, such as the basal ganglia, cerebral cortex, and cerebellar cortex. However, in some regions, such as the substantia nigra (SN), SLC20A2 was also expressed at high levels, but IBGC patients never show a calcification in this area. For this reason, other factors may also be involved in the calcification process. Villa-Bellosta et al. showed that SLC20A2 function could be regulated by acidosis 
. We performed MRS to determine the local lactate level. Lactate is a marker of metabolic activity, and abnormal accumulation of lactate may indicate regional acidosis. The 4-year-old girl with minimal calcification was evaluated with MRS, and we did not find any increase in lactate level in the calcified areas or any difference in lactate level between the calcified area and the unaffected area. In addition, other studies have shown no significant regional variations in pH value within the human brain 
. As a result, acidosis does not seem to be involved in the regulation of Pi homeostasis in the brain.
Pathological analysis of IBGC individuals showed that the calcification of IBGC involved the media and intima of cerebral vessels, including small arteries, small veins and capillaries 
. This is consistent with the minimal and late onset of the symptoms because no neuronal damage occurs during the early stages of IBGC. Studies on the pathogenesis of vascular calcification induced by phosphate showed that SLC20A1 has a determinant role in the mineralization of vascular cells in vitro
. For this reason, we propose that both SLC20A1 and SLC20A2 might be involved in the pathogenesis of FIBGC. It has been previously demonstrated that both SLC20A1 and SLC20A2 are expressed in the brain but in different patterns 
. The basal ganglia area expresses high levels of SLC20A2 but low levels of SLC20A1, which may make this area vulnerable to SLC20A2
mutation. Researchers have also found that SLC20A2 expression cannot be regulated in the brain, which makes SLC20A2 an ideal target gene for IBGC 
. Although the SN has an expression pattern similar to that shown by SLC20A1 and SLC20A2 in the basal ganglia, SLC20A1 expression can be up-regulated in this area 
. This may compensate for the mutation of SLC20A2
and maintain the local Pi homeostasis. We speculate that, although SLC20A2 is widely expressed outside brain, the co-expressed SLC20A1 may compensate for mutations in SLC20A2
and render the cells outside of the brain resistant to SLC20A2
mutations. This may be an explanation for why no calcification takes place outside the brain in IBGC patients. The unique expression of both SLC20A1 and SLC20A2 may explain the specific calcification pattern observed in IBGC.
In conclusion, we identified a novel SLC20A2 mutation, which causes a significant decrease in SLC20A2 mRNA expression. Our results indicate that the insufficient SLC20A2 expression caused by the SLC20A2 mutation is the molecular basis for the pathogenesis of IBGC and that insufficient SLC20A2 expression may lead to abnormal local Pi homeostasis and then to calcification of the basal ganglia. To explain the unique calcification pattern of IBGC patients, we here propose a hypothesis that the regional expression pattern of SLC20A1and SLC20A2 may be the molecular basis for IBGC. Our hypothesis has partial support from our results and the literature reviews. However, this hypothesis requires further careful investigation.