Analysis of Gene Expression Pattern and Neuroanatomical Correlates for SLC20A2 (PiT-2) Shows a Molecular Network with Potential Impact in Idiopathic Basal Ganglia Calcification (“Fahr’s Disease”)

Abstract

Familial idiopathic basal ganglia calcification (FIBGC), also known as "Fahr's disease," is a neuropsychiatric disorder with motor and cognitive symptoms. It is characterized pathologically by bilateral calcification most commonly in the basal ganglia and also in other brain regions such as the thalamus and cerebellum. A recent report by Wang et al. (2012) discovered multiple families with FIBGC carrying mutations in the SLC20A2 gene, encoding the inorganic phosphate transporter PiT-2, which segregated in an autosomal dominant pattern. To understand further the role of SLC20A2 in FIBGC brain pathology, here we described the gene expression pattern across the whole brain for SLC20A2, using the Allen Institute Human Brain Atlas database. Microarray analysis provided evidence that the neuroanatomical pattern of expression for SLC20A2 is highest in the regions most commonly affected in FIBGC. Neuroanatomical regions that demonstrated high correlation or anti-correlation with SLC20A2 expression also showed a molecular network with potential to explain the limited neuroanatomical distribution of calcifications in IBGC. Lastly, these co-expression networks suggest additional further candidate genes for FIBGC.

Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm

“…Interestingly, Vamp1 (also known as Synaptobrevin1) may play a role in Pi-dependent endocytosis. Vamp1 is expressed in the YS and closely parallels expression of PiT-2 in the brain (da Silva et al, 2013). Vamp1 splice-isoforms vary in sequence and function.…”

“…Additionally, PiT-1 compensation has been suggested as a potential pathogenic mechanism for development of Familial Idiopathic Basal Ganglia Calcification (FIBGC) in human cases associated with mutated PiT-2 sequences (da Silva et al, 2013; Hsu et al, 2013; Wang et al, 2012; Zhang et al, 2013). For these reasons, the mechanisms controlling compensatory PiT expression are of interest.…”

“…Furthermore, abnormal levels of PiT gene expression may promote FIBGC. Large subsets of patients with FIBGC were recently found to contain deleterious mutations in PiT-2 (da Silva et al, 2013; Hsu et al, 2013; Wang et al, 2012; Zhang et al, 2013), which has been suggested to result in compensatory PiT-1 overexpression and subsequent disease-related calcification. Interestingly, PiT-1 is not capable of compensating for loss of PiT-2 in FIBGC.…”

An Externally Accessible Linker Region in the Sodium-Coupled Phosphate Transporter PiT-1 (SLC20A1) is Important for Transport Function

“…Importantly, PiT-2 has been localized to the apical membrane of renal proximal tubule cells in the mammalian kidney and displays a different regulatory response from the SLC34 family members to changes in dietary P i [19,20], although its precise role in renal P i handling is yet to be fully elucidated [21]. Most recently, a role for PiT-2 in the CNS has been identified, whereby mutations in human PiT-2 (SLC20A2) have been implicated in familial idiopathic basal ganglia calcification (Fahr's disease) [22,23]. …”

Brain calcifications and PCDH12 variants

“…2,3 Heterozygous variants causing autosomal dominant PFBC in up to 50% of the families were identified in 4 genes: SLC20A2 , PDGFRB , PDGFB , and XPR1 . 4–8 We previously searched for genes with a cerebral expression pattern similar to the PFBC major causative gene SLC20A2 using the Allen Brain Atlas (brain-map.org/), 9,10 observing a higher SLC20A2 expression in regions affected by calcifications in PFBC. PCDH12 was singled out with the highest significant correlation, 10 and a follow-up analysis with additional brains still shows PCDH12 as the most similar pattern to SLC20A2 , even when compared with the other known PFBC causative genes (table e-1 at Neurology.org/ng).…”