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Idiopathic basal ganglia calcification (IBGC) or primary familial brain calcification is a rare genetic condition characterized by an autosomal dominant inheritance pattern and the presence of bilateral calcifications in the basal ganglia, thalami, cerebellum and cerebral subcortical white matter. The syndrome is genetically and phenotypically heterogeneous. Causal mutations have been identified in four genes: SLC20A2, PDGFRB, PDGFB and XPR1. A variety of progressive neurological and psychiatric symptoms have been described, including cognitive impairment, movement disorders, bipolar disorder, chronic headaches and migraine, and epilepsy. Here we describe a family with a novel SLC20A2 mutation mainly presenting with neurological symptoms including cortical myoclonus and epilepsy. While epilepsy, although rare, has been reported in patients with IBGC associated with SLC20A2 mutations, cortical myoclonus seems to be a new manifestation.

The common cellular origin between bone marrow adipocytes (BMAds) and osteoblasts contributes to the intimate link between bone marrow adipose tissue (BMAT) and skeletal health. An imbalance between the differentiation ability of BMSCs towards one of the two lineages occurs in conditions like aging or osteoporosis, where bone mass is decreased. Recently, we showed that the sodium-phosphate co-transporter PiT2/SLC20A2 is an important determinant for bone mineralization, strength and quality. Since bone mass is reduced in homozygous mutant mice, we investigated in this study whether the BMAT was also affected in PiT2-/- mice by assessing the effect of the absence of PiT2 on BMAT volume between 3 and 16 weeks, as well as in an ovariectomy-induced bone loss model. Here we show that the absence of PiT2 in juveniles leads to an increase in the BMAT that does not originate from an increased adipogenic differentiation of bone marrow stromal cells. We show that although PiT2-/- mice have higher BMAT volume than control PiT2+/+ mice at 3 weeks of age, BMAT volume do not increase from 3 to 16 weeks of age, leading to a lower BMAT volume in 16-week-old PiT2-/- compared to PiT2+/+ mice. In contrast, the absence of PiT2 does not prevent the increase in BMAT volume in a model of ovariectomy-induced bone loss. Our data identify SLC20a2/PiT2 as a novel gene essential for the maintenance of the BMAd pool in adult mice, involving mechanisms of action that remain to be elucidated, but which appear to be independent of the balance between osteoblastic and adipogenic differentiation of BMSCs.

BACKGROUND Familial idiopathic basal ganglia calcification (FIBGC) is a rare autosomal dominant disorder that causes bilateral calcification of the basal ganglia and/or cerebellar dentate nucleus, among other locations. CASE SUMMARY The aim of this study is to report 10 cases of FIBGC observed in a single family. Seven patients showed calcification on their computed tomography scan, and all of these patients carried the SLC20A2 mutation. However, individuals without the mutation did not show calcification. Three patients among the 7 with calcification were symptomatic, while the remaining 4 patients were asymptomatic. Additionally, we longitudinally observed 10 subjects for ten years. In this paper, we mainly focus on the clinical course and neuroradiological findings in the proband and her son. CONCLUSION The accumulation of more case reports and further studies related to the manifestation of FIBGC are needed.

Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in SLC20A2 [NM_001257180.2; c.806delC, p.(Pro269Glnfs*49) and c.1154delG, p.(Ser385Ilefs*70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in PDGFB were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to SLC20A2 haploinsufficiency among the affected family members. The c.456+1G>C mutation in PDGFB resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in SLC20A2 and PDGFB, which broadened and enriched the PFBC mutation spectrum.

BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations inSLC20A2are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whetherSlc20a2knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities inSlc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 inSlc20a2-HO mice, but were seldom found inSlc20a2heterozygous knockout (Slc20a2-HE) mice, even at extremely old age.Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different betweenSlc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those inSlc20a2-HO mice. Therefore,Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

Background Primary familial brain calcification (PFBC) is a rare inheritable neurodegenerative disease characterized by bilateral calcification in different brain regions and by a range of neuropsychiatric symptoms. Six causative genes of PFBC (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified. Methods Sanger sequencing was used to identify the causative genes associated with PFBC in this study. Results We describe the first PFBC case with both SLC20A2 and PDGFRB heterozygous mutations. Notably, this patient with the digenic mutation (who was only 5 years old) showed severe brain calcification and migraine, whereas the patient's parents, who each carried a heterozygous mutation in SLC20A2 or PDGFRB, exhibited varying degrees of brain calcification but were clinically asymptomatic. Conclusion This case highlights the digenic influences on the characteristics of PFBC patients., We report a family in which the members have various genetic states and manifestations of PFBC. Notably, the proband carrying the SLC20A2 and PDGFRB heterozygous mutations showed more severe brain calcification and earlier onset age of clinical symptoms than her family members, highlighting digenic influences on the characteristics of PFBC patients.

Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease or primary familial brain calcification, manifests as bilaterally symmetric calcifications in the brain. Clinical symptoms range from movement disorders to cognitive impairment and psychiatric symptoms. Since 2012, IBGC has been reported as an inherited disorder with several causative genes, including SLC20A2; however, the genotype-phenotype association remains unclear. Furthermore, longitudinal follow-up studies investigating the prognosis of neuropsychiatric symptoms in IBGC are lacking. A 36-year-old woman who experienced recurrent psychosis since the age of 30 years was admitted to our hospital. Her symptoms included delusions, hallucinations, disorganized speech, and grossly disorganized behavior. Cranial CT revealed calcification of the bilateral basal ganglia and dentate nucleus. The possibility of metabolic or endocrinological disorders causing secondary calcification was excluded via laboratory examinations. The genetic analysis revealed SLC20A2 mutation, and therefore, she was diagnosed with definite IBGC. At the age of 37, 42, and 43 years, similar psychosis recurred due to a decrease in medication. Each episode was relieved within one week with a low dose of risperidone (1.5-2 mg/day p.o.). Eventually, remission was maintained with risperidone (1.5 mg/day). To our knowledge, genetically confirmed case of IBGC with psychosis has been rarely reported. Recurrent psychosis can be the sole symptom of SLC20A2-associated IBGC and may be remitted with a low dose of risperidone. Literature review including eight case reports shows no superiority between medications. Although our case indicates that a low dose of antipsychotics can alleviate symptoms without any side effects and should be continued to prevent relapse in some patients with IBGC, there has been still shortage of the clinical evidence. Further longitudinal studies on genotype-phenotype associations may expedite personalized medicine for patients with IBGC.

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

Aims This study aimed to investigate the effect of solute carrier family 20 member 2 (SLC20A2) gene mutation (identified from a hereditary multiple exostoses family) on chondrocyte proliferation and differentiation. Methods ATDC5 chondrocytes were cultured in insulin-transferrin-selenium medium to induce differentiation. Cells were transfected with pcDNA3.0 plasmids with either a wild-type (WT) or mutated (MUT) SLC20A2 gene. The inorganic phosphate (Pi) concentration in the medium of cells was determined. The expression of markers of chondrocyte proliferation and differentiation, the Indian hedgehog (Ihh), and parathyroid hormone-related protein (PTHrP) pathway were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Results The expression of SLC20A2 in MUT group was similar to WT group. The Pi concentration in the medium of cells in MUT group was significantly higher than WT group, which meant the SLC20A2 mutation inhibited Pi uptake in ATDC5 chondrocytes. The proliferation rate of ATDC5 chondrocytes in MUT group was greater than WT group. The expression of aggrecan (Acan), α-1 chain of type II collagen (COL2A1), and SRY-box transcription factor 9 (SOX9) were higher in MUT group than WT group. However, the expression of Runt-related transcription factor 2 (Runx2), α-1 chain of type X collagen (COL10A1), and matrix metallopeptidase 13 (MMP13) was significantly decreased in the MUT group. Similar results were obtained by Alcian blue and Alizarin red staining. The expression of Ihh and PTHrP in MUT group was higher than WT group. An inhibitor (cyclopamine) of Ihh/PTHrP signalling pathway inhibited the proliferation and restored the differentiation of chondrocytes in MUT group. Conclusion A mutation in SLC20A2 (c.C1948T) decreases Pi uptake in ATDC5 chondrocytes. SLC20A2 mutation promotes chondrocyte proliferation while inhibiting chondrocyte differentiation. The Ihh/PTHrP signalling pathway may play an important role in this process. Cite this article: Bone Joint Res 2020;9(11):751–760.

Background: Idiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients. Methods: Clinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype. Results: A novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1st and 8th exons; the second common one is PDGFB where the hot spot covered a length of 220–230 bp localized on the 2nd exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries. Conclusions: There is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease. Key words: Genotype; Idiopathic Basal Ganglia Calcification; Phenotype; SLC20A2

International audience; Purpose of ReviewDespite the important progress made in understanding the regulation of phosphate (Pi) homeostasis over the past 20 years, the mechanisms underlying the very early step leading to the regulating cascade involving multiple hormones (PTH, vitamin D, FGF23) and organs (kidney, intestine, bone, parathyroid glands) are not deciphered. Particularly, knowledge on the Pi-sensing mechanism present within or on the surface of the cell that is able to detect changes in serum or local Pi concentrations and trigger an appropriate FGF23 synthesis/secretion is limited or absent.Recent FindingsSeveral molecular actors have recently been involved as potential key players in Pi sensing and Pi-dependent control of FGF23 secretion. Among them, the PiT1/Slc20a1 and PiT2/Slc20a2 proteins are standing out.SummaryWe are just beginning to accumulate in vitro and in vivo data that will provide invaluable molecular tools to explore and understand the integrated response of the body to variations of Pi concentration.

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.

Idiopathic basal ganglia calcification (IBGC), commonly referred to as Fahr's disease, is a rare neurological disorder characterized by the abnormal, symmetrical, and bilateral calcification of the basal ganglia and other brain regions. Patients typically present in their forties and fifties with various neurologic and/or psychiatric symptoms, including movement disorders, Parkinsonism, psychosis, and depression. The pathophysiology of this disease is not completely understood; however, several gene mutations have been identified in the pathogenesis of Fahr's disease. These mutations display an autosomal dominant inheritance pattern. Furthermore, the regional phenotypic expression of calcifications differs greatly from patient to patient, as do their clinical presentations. Here, we describe a patient who presented with psychiatric manifestations and imaging consistent with Fahr's disease.

Background: Idiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients. Methods: Clinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype. Results: A novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1st and 8th exons; the second common one is PDGFB where the hot spot covered a length of 220–230 bp localized on the 2nd exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries. Conclusions: There is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease.

Primary brain calcification (PBC) is a neurodegenerative disorder characterized by calcium-phosphate deposits in the basal ganglia and often also other areas of the brain. The prevalent clinical manifestations are cognitive impairment, neuropsychiatric symptoms, and movement disorders. In recent years, monoallelic variants in SLC20A2, which encodes the type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2), have been linked to the familial form of PBC in 40-50% of the families reported worldwide as well as to sporadic cases of PBC. Further insight into the disease mechanism is, however, needed. Based on co-expression studies of wild-type and variant PiT2 in Xenopus laevis oocytes, the molecular disease mechanism associated with SLC20A2 missense variants has formerly been suggested to be haploinsufficiency. We have here used mammalian cells isolated from a Slc20a2 -/- mouse and co-expression of human wild-type and variant PiT2. Two of the variants studied have both been reported twice in unrelated PBC cases: PiT2D28N in two sporadic cases and PiT2E575K in a familial and a sporadic case. We find that in mammalian cells, the analyzed SLC20A2 missense variants can exert their effect in a dominant negative manner resulting in decreased wild-type PiT2 Pi transport. Thus, compared to monoallelic lack of functional PiT2 protein expression, which reasonably points towards haploinsufficiency, certain SLC20A2 missense variants may be more detrimental for cellular Pi uptake and potentially contribute to an earlier disease onset and/or a more severe phenotype as observed for Slc20a2 -/- mice compared to Slc20a2 +/- mice.

Introduction There are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2 , PDGFB, PDGFRB and XPR1 . In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods We performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2 , PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.

Dietary potassium (K) deficiency is accompanied by phosphaturia and decreased renal brush border membrane (BBM) vesicle sodium (Na)-dependent phosphate (Pi) transport activity. Our laboratory previously showed that K deficiency in rats leads to increased abundance in the proximal tubule BBM of the apical Na-Pi cotransporter NaPi-IIa, but that the activity, diffusion, and clustering of NaPi-IIa could be modulated by the altered lipid composition of the K-deficient BBM (Zajicek HK, Wang H, Puttaparthi K, Halaihel N, Markovich D, Shayman J, Beliveau R, Wilson P, Rogers T, Levi M. Kidney Int 60: 694–704, 2001; Inoue M, Digman MA, Cheng M, Breusegem SY, Halaihel N, Sorribas V, Mantulin WW, Gratton E, Barry NP, Levi M. J Biol Chem 279: 49160–49171, 2004). Here we investigated the role of the renal Na-Pi cotransporters NaPi-IIc and PiT-2 in K deficiency. Using Western blotting, immunofluorescence, and quantitative real-time PCR, we found that, in rats and in mice, K deficiency is associated with a dramatic decrease in the NaPi-IIc protein abundance in proximal tubular BBM and in NaPi-IIc mRNA. In addition, we documented the presence of a third Na-coupled Pi transporter in the renal BBM, PiT-2, whose abundance is also decreased by dietary K deficiency in rats and in mice. Finally, electron microscopy showed subcellular redistribution of NaPi-IIc in K deficiency: in control rats, NaPi-IIc immunolabel was primarily in BBM microvilli, whereas, in K-deficient rats, NaPi-IIc BBM label was reduced, and immunolabel was prevalent in cytoplasmic vesicles. In summary, our results demonstrate that decreases in BBM abundance of the phosphate transporter NaPi-IIc and also PiT-2 might contribute to the phosphaturia of dietary K deficiency, and that the three renal BBM phosphate transporters characterized so far can be differentially regulated by dietary perturbations.

Background Primary familial brain calcification (PFBC) is a rare neurodegenerative disease characterized by bilateral calcifications mostly located in the basal ganglia and in the thalami, cerebellum and subcortical white matter. Clinical manifestations of this disease include a large spectrum of movement disorders and neuropsychiatric disturbances. PFBC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. Three causative genes have been reported: SLC20A2, PDGFRB and PDGFB. Objective We screened three PFBC Italian families for mutations in the SLC20A2, PDGFRB and PDGFB genes. Methods Phenotypic data were obtained by neurologic examination, CT scan and magnetic resonance imaging. Mutation screening of SLC20A2, PDGFRB and PDGFB was performed by sequencing. Results We identified a new heterozygous deletion c.21_21delG (p.L7Ffs*10) in SLC20A2 gene in one of these families. No mutations were detected in the other two families. Conclusions Our data confirm that mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

BackgroundPrimary familial brain calcification (PFBC) is a rare autosomal dominant disorder with bilateral calcification of basal ganglia and other cerebral regions, movement disorders, and neuropsychiatric disturbances. So far, three causative genes have been discovered: SLC20A2, PDGFRB and PDGFB, accounting for approximately 50% of cases. MethodsSeven unrelated families with primary brain calcification were recruited to undergo clinical and genetic analysis, including Sanger sequencing of SLC20A2, PDGFRB, and PDGFB, and copy number analysis of SLC20A2. ResultsMutations in SLC20A2 have been detected in three families: p.Glu368Glyfs*46, p.Ser434Trp, and p.Thr595Met. Intrafamilial phenotype variability has been observed. In spite of this, we found similar neuroimaging pattern among members of the same family. ConclusionsThis molecular analysis expands the mutational spectrum of SLC20A2, which remains the major causative gene of primary familial brain calcification, and suggests the existence of disease-causing mutations in at least another, still unknown gene. (c) 2014 International Parkinson and Movement Disorder Society

Mutations in the SLC20A2-gene encoding the inorganic phosphate (Pi) transporter PiT2 can explain approximately 40 % of the familial cases of the rare neurodegenerative disorder primary familial brain calcification (Fahr’s disease). The disease characteristic, cerebrovascular-associated calcifications, is also present in Slc20a2-knockout (KO) mice. Little is known about the specific role(s) of PiT2 in the brain. Recent in vitro studies, however, suggest a role in regulation of the [Pi] in cerebrospinal fluid (CSF). We here show that Slc20a2-KO mice indeed have a high CSF [Pi] in agreement with a role of PiT2 in Pi export from the CSF. The implications in relation to disease mechanism are discussed.

Familial idiopathic basal ganglia calcification (FIBGC) is a neurodegenerative disorder with neuropsychiatric and motor symptoms. Deleterious mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), were recently linked to FIBGC in almost 50% of the families reported worldwide. Here, we show that knockout of Slc20a2 in mice causes calcifications in the thalamus, basal ganglia, and cortex, demonstrating that reduced PiT2 expression alone can cause brain calcifications.