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The Golgi apparatus is vital for protein modification and molecular trafficking. It is essential for nerve development and activity, and damage thereof is implicated in many neurological diseases. Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disease characterized by multiple brain calcifications. SLC20A2 , which encodes the inorganic phosphate transporter 2 (PiT-2) protein, is the main pathogenic gene in PFBC. The PiT-2 protein is a sodium-dependent phosphate type III transporter, and dysfunction leads to a deficit in the cellular intake of inorganic phosphate (Pi) and calcium deposits. Whether the impaired Golgi apparatus is involved in the PFBC procession requires elucidation. In this study, we constructed induced pluripotent stem cells (iPSCs) derived from two PFBC patients with different SLC20A2 gene mutations (c.613G > A or del exon10) and two healthy volunteers as dependable cell models for research on pathogenic mechanism. To study the mechanism, we differentiated iPSCs into neurons and astrocytes in vitro. Our study found disruptive Golgi structure and damaged autophagy in PFBC neurons with increased activity of mTOR. We also found damaged mitochondria and increased apoptosis in the PFBC dopaminergic neurons and astrocytes. In this study, we prove that dysfunctional PiT-2 leads to an imbalance of cellular Pi, which may disrupt the Golgi apparatus with impaired autophagy, mitochondria and apoptosis in PFBC. Our study provides a new avenue for understanding nerve damage and pathogenic mechanism in brain calcifications. [Display omitted] • Neurons and astrocytes differentiated from PFBC-patient-derived iPSCs have same gene mutation and symptoms with the donors. • Dysfunctional PiT-2 caused to Golgi disruption in PFBC. • Impaired autophagy and mitochondria also participated in PFBC. [ABSTRACT FROM AUTHOR]

Tics, Tourettism, primary familial brain calcification, SLC20A2 Keywords: tics; Tourettism; primary familial brain calcification; SLC20A2 EN tics Tourettism primary familial brain calcification SLC20A2 1152 1154 3 07/21/23 20230701 NES 230701 Primary Familial Brain Calcification (PFBC) is a genetic disorder characterized by bilateral abnormal calcium deposition in one or more regions of the brain in the absence of a secondary cause.[1] Its genotypic and phenotypic spectrum continues to evolve and be elucidated.[2] Here, we describe a patient with PFBC due to a pathogenic variant in the solute carrier family 20 member 2 ( I SLC20A2) i gene who presented with adult-onset Tourettism. Imaging in the patient demonstrated bilateral basal ganglia, posterior thalami, and frontal and parietal subcortical white matter calcifications (Fig. [Extracted from the article]

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet‐derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet‐derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis‐regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one‐third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal‐dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype–phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered. • Brain calcification was variable, predominantly seen in central structures. • Most patients (76%) exhibited motor, psychiatric, and/or cognitive symptoms. • There was clinical progression in most but only a modest increase in calcification. • We identified a novel pathogenic genetic variant in the SLC20A2 gene. [ABSTRACT FROM AUTHOR]

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.

Abstract 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.

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 in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout 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 in Slc20a2-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.ResultsSlc20a2 homozygous 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 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous 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 between Slc20a2-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 in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Primary 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 in SLC20A2 are the major genetic causes of PFBC. Objective: This study aimed to investigate whether Slc20a2 knockout 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 in Slc20a2 -deficient mice. Methods: Brain 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. Results: Slc20a2 homozygous 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 in Slc20a2 -HO mice, but were seldom found in Slc20a2 heterozygous 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 between Slc20a2 -HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations. Conclusion: The human PFBC-related phenotypes were highly similar to those in Slc20a2 -HO mice. Therefore, Slc20a2 -HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments. [ABSTRACT FROM AUTHOR]

Objective: Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes.Methods: After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9).Results: The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P < 0.001). This was comparable with that of patients carrying an SLC20A2 premature stop codon (63.4%; P < 0.001). The proband exhibited a 39.3% decrease of inorganic phosphate uptake in blood (P = 0.015). In HEK293 cells, we observed a 39.8% decrease in relative SLC20A2 mRNA levels after normalization on DNA copy number (P < 0.001).Discussion: We identified a deletion of an enhancer of SLC20A2 expression, with carriers showing haploinsufficiency in similar ranges to loss-of-function alleles, and we observed reduced mRNA levels after deleting this element in a cellular model. We propose a 3-step strategy to identify and easily assess the effect of such events. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

• A rare splicing mutation related to PFBC in SLC20A2 (c.730 + 1G > A) was found. • The splicing mutation leads to exon 6 skipping in SLC20A2. • The mutation results in a 39 amino acid deletion in SLC20A2 protein. Primary familial brain calcification (PFBC) is a rare degenerative disease characterized by symmetrical bilateral calcinosis in the basal ganglia and other brain regions. It has an autosomal dominant inheritance pattern in most cases and exhibits genetic heterogeneity. Previous studies reported that SLC20A2, PDGFRB, PDGFB , XPR1 and MYORG are associated with PFBC, with SLC20A2 the main culprit. However, other mutations may also cause PFBC. Here, we performed a study to reveal the contributing mutations that gave rise to PFBC in a Chinese PFBC family. We recruited a PFBC family consisting of eight patients and eight healthy family members across three generations. Whole-exome sequencing, Sanger sequencing and RT-PCR were used to detect the genetic mutations. Whole-exome sequencing revealed that c.730 + 1G > A of SLC20A2 was the candidate pathogenic mutation for the proband in this family. Genomic DNA PCR amplification and Sanger sequencing confirmed that all the patients from the family carried this mutation, while the healthy subjects in the family did not. Complementary DNA (cDNA) PCR amplification and Sanger sequencing confirmed that the patients had a mutation that caused exon 6 skipping in SLC20A2. We identified a SLC20A2 splicing variant (c.730 + 1G > A) in a PFBC family. This mutation led to an alternative splicing event that skipped exon 6 in SLC20A2. [ABSTRACT FROM AUTHOR]

Primary familial brain calcification (PFBC) is a rare neurological disorder. Mutations in five genes (SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG) have been linked to PFBC. Here, we used SYBR green‐based real‐time quantitative polymerase chain reaction (PCR) assay and denaturing high‐performance liquid chromatography analysis to detect copy number variants (CNVs) in 20 unrelated patients with PFBC, negatively sequenced for the five known genes. We identified three deletions in SLC20A2, including a large de novo full gene deletion and two exonic deletions confined to exon 2 and exon 6, respectively. Subsequent linked‐read whole‐genome sequencing of the patient with the large deletion showed a 1.7 Mb heterozygous deletion which removed the entire coding regions of SLC20A2 as well as 21 other genes. In the family with a deletion of exon 6, a missense variant of uncertain significance (SLC20A2: p.E267Q) also co‐segregated with the disease. Functional assay showed the deletion could result in significantly impaired phosphate transport, whereas the p.E267Q variant did not. Our results confirm that deletion in SLC20A2 is a causal mechanism for PFBC and highlight the importance of functional study for classifying a rare missense variant as (likely) pathogenic. [ABSTRACT FROM AUTHOR]

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC. We made a genetic diagnosis in 16.8% of PFBC probands and identified 30 mutations; Mutations in SLC20A2 are the major cause of PFBC, while the other three genes are relatively rare; Our findings also strongly support crucial roles of phosphate transport impairment in the pathogenies of PFBC. [ABSTRACT FROM AUTHOR]

Objectives Primary familial brain calcification ( PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes ( SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients. Materials and methods A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome ( WES) and whole-genome sequencing ( WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis. Results Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5′ UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes. Conclusions Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations ( CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (P) 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 P 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 P uptake and potentially contribute to an earlier disease onset and/or a more severe phenotype as observed for Slc20a2 mice compared to Slc20a2 mice. [ABSTRACT FROM AUTHOR]

Highlights • We present a Japanese family with primary familial brain calcification (PFBC). • Whole-exome sequencing identified a novel frameshift mutation in SLC20A2. • The proband presented with a transient ischemic attack (TIA). • PFBC may be associated with secondary ischemic stroke, including TIA. [ABSTRACT FROM AUTHOR]

Idiopathic basal ganglia calcification (IBGC), or Fahr's disease, is a neurological disorder characterized by widespread calcification in the brain. Recently, several causative genes have been identified, but the histopathologic features of the brain lesions and expression of the gene products remain unclear. Here, we report the clinical and autopsy features of a 62-year-old Japanese man with familial IBGC, in whom an SLC20A2 mutation was identified. The patient developed mild cognitive impairment and parkinsonism. A brain CT scan demonstrated abnormal calcification in the bilateral basal ganglia, thalami and cerebellum. An MRI study at this point revealed glioblastoma, and the patient died 6 months later. At autopsy, symmetric calcification in the basal ganglia, thalami, cerebellar white matter and deeper layers of the cerebral cortex was evident. The calcification was observed in the tunica media of small arteries, arterioles and capillaries, but not in veins. Immunohistochemistry using an antibody against type III sodium-dependent phosphate transporter 2 (PiT-2), the SLC20A2 product, demonstrated that astrocytic processes were labeled in several regions in control brains, whereas in the patient, reactivity in astrocytes was apparently weak. Immunoblotting demonstrated a marked decrease of PiT-2 in the patient. There are few autopsy reports of IBGC patients with confirmation of the genetic background. The autopsy features seem informative for better understanding the histogenesis of IBGC lesions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The genetic understanding of primary familial brain calcification (PFBC) has increased considerably in recent years due to the finding of causal genes like SLC20A2 , PDGFRB and PDGFB . The phenotype of PFBC is complex and has as of yet been poorly delineated. The most common clinical presentations include movement disorders, cognitive symptoms and psychiatric conditions. We report a family including two sisters with brain calcifications due to a variant in SLC20A2 and generalized tonic-clonic seizures as the principal phenotypic trait. Methods The affected siblings underwent whole exome sequencing and candidate variants and cosegregation in the family were validated by Sanger sequencing. Results Both siblings and their asymptomatic father were heterozygous for a variant in SLC20A2 . The siblings also had a variant in CHRNB2 , a known epilepsy gene associated with autosomal dominant frontal lobe epilepsy, which they had inherited from the mother. Conclusions To our knowledge, the reported siblings represent the third and fourth subjects with confirmed SLC20A2 variants exhibiting epilepsy as a phenotypic trait. Our findings support seizures as part of the phenotypic spectrum of SLC20A2- related PFBC. However, the present phenotype may also result from additional genetic influence, such as the identified missense variant in CHRNB2 . [ABSTRACT FROM AUTHOR]

ABSTRACT Background Primary 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. Methods Seven 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. Results Mutations 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. Conclusions This 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. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

The article focuses on mammalian xenotropic polytropic virus receptor 1 (XPR1) gene as the additional genetic cause of primary familial brain calcifications (PFBC), a genetically heterogenous disorder transmitted in autosomal-dominant fashion. Topics discussed include the sequencing of XPR1 in sporadic and familial case, the encodes of the XPR1 gene to a cell-surface multipass membrane protein and identification of the potential treatments for the untreatable disorder.