Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8.

Phosphate (Pi) serves countless metabolic pathways and is involved in macromolecule synthesis, energy storage, cellular signaling, and bone maintenance. Herein, we describe the coordination of Pi uptake and efflux pathways to maintain mammalian cell Pi homeostasis. We discover that XPR1, the presumed Pi efflux transporter, separately supervises rates of Pi uptake. This direct, regulatory interplay arises from XPR1 being a binding partner for the Pi uptake transporter PiT1, involving a predicted transmembrane helix/extramembrane loop in XPR1, and its hitherto unknown localization in a subset of intracellular LAMP1-positive puncta (named "XLPVs"). A pharmacological mimic of Pi homeostatic challenge is sensed by the inositol pyrophosphate IP8, which functionalizes XPR1 to respond in a temporally hierarchal manner, initially adjusting the rate of Pi efflux, followed subsequently by independent modulation of PiT1 turnover to reset the rate of Pi uptake. These observations generate a unifying model of mammalian cellular Pi homeostasis, expanding opportunities for therapeutic intervention.

XPR1: a regulator of cellular phosphate homeostasis rather than a Pi exporter.

Phosphate (Pi) is an essential nutrient, and its plasma levels are under tight hormonal control. Uphill transport of Pi into cells is mediated by the two Na-dependent Pi transporter families SLC34 and SLC20. The molecular identity of a potential Pi export pathway is controversial, though XPR1 has recently been suggested by Giovannini and coworkers to mediate Pi export. We expressed XPR1 in Xenopus oocytes to determine its functional characteristics. Xenopus isoforms of proteins were used to avoid species incompatibility. Protein tagging confirmed the localization of XPR1 at the plasma membrane. Efflux experiments, however, failed to detect translocation of Pi attributable to XPR1. We tested various counter ions and export medium compositions (pH, plasma) as well as potential protein co-factors that could stimulate the activity of XPR1, though without success. Expression of truncated XPR1 constructs and individual domains of XPR1 (SPX, transmembrane core, C-terminus) demonstrated downregulation of the uptake of Pi mediated by the C-terminal domain of XPR1. Tethering the C-terminus to the transmembrane core changed the kinetics of the inhibition and the presence of the SPX domain blunted the inhibitory effect. Our observations suggest a regulatory role of XPR1 in cellular Pi handling rather than a function as Pi exporter. Accordingly, XPR1 senses intracellular Pi levels via its SPX domain and downregulates cellular Pi uptake via the C-terminal domain. The molecular identity of a potential Pi export protein remains therefore elusive.

New Evidence Suggests a Much Complex Classification for the Genetic Pattern of Inheritance in Primary Brain Calcification.

Primary familial brain calcification (PFBC), often called Fahr's disease, is a condition in which calcium phosphate accumulates in the brain, mainly in the basal ganglia, thalamus, and cerebellum, and without the association of any metabolic or infectious cause. Patients present a variety of neurological and psychiatric disorders, usually during adulthood. The disease is caused by autosomal dominant pathogenic variants in genes such as SLC20A2, PDGFRB, PDGFB, and XPR1. MYORG and JAM2 are the other genes linked to homozygous patterns of inheritance. Here, we briefly discuss the recent cases reported by Ceylan et al. (2022) and Al-Kasbi et al. (2022), which challenge the current association with two previous genes and a clear pattern of inheritance. Ceylan et al. report a new biallelic variant related to a pathogenic variant in the SLC20A2 gene, which is typically associated with a heterozygous mutation pattern. The affected siblings displayed a severe and early onset of the disease, revealing a phenotype similar to that seen in CMV infections, often named as pseudo-TORCH. Furthermore, a study of genes related to intellectual disability conducted by Al-Kasbi et al. demonstrated that the biallelic manifestation of the XPR1 gene was associated with early symptoms, leading to the belief that the homozygous pattern of genes responsible for causing PFBC with an autosomal dominant pattern may also be linked to early-onset manifestations of PFBC. Further studies might explore the variety of clinical presentations linked to PFBC genes, especially if we pay attention to complex patterns of inheritance, reinforcing the need for a more detailed bioinformatic analysis.

Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis.

Calcification of the cerebral microvessels in the basal ganglia in the absence of systemic calcium and phosphate imbalance is a hallmark of primary familial brain calcification (PFBC), a rare neurodegenerative disorder. Mutation in genes encoding for sodium-dependent phosphate transporter 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), platelet-derived growth factor B (PDGFB), platelet-derived growth factor receptor beta (PDGFRB), myogenesis regulating glycosidase (MYORG), and junctional adhesion molecule 2 (JAM2) are known to cause PFBC. Loss-of-function mutations in XPR1, the only known inorganic phosphate exporter in metazoans, causing dominantly inherited PFBC was first reported in 2015 but until now no studies in the brain have addressed whether loss of one functional allele leads to pathological alterations in mice, a commonly used organism to model human diseases. Here we show that mice heterozygous for Xpr1 (Xpr1WT/lacZ ) present with reduced inorganic phosphate levels in the cerebrospinal fluid and age- and sex-dependent growth of vascular calcifications in the thalamus. Vascular calcifications are surrounded by vascular basement membrane and are located at arterioles in the smooth muscle layer. Similar to previously characterized PFBC mouse models, vascular calcifications in Xpr1WT/lacZ mice contain bone matrix proteins and are surrounded by reactive astrocytes and microglia. However, microglial activation is not confined to calcified vessels but shows a widespread presence. In addition to vascular calcifications, we observed vessel tortuosity and transmission electron microscopy analysis revealed microangiopathy-endothelial swelling, phenotypic alterations in vascular smooth muscle cells, and thickening of the basement membrane.

Brain Calcifications: Genetic, Molecular, and Clinical Aspects.

Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium-phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood-brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.

Bioinformatics analyses proposed xenotropic and polytropic retrovirus receptor 1 as a potential diagnostic and prognostic biomarker and immunotherapeutic target in head and neck squamous cell carcinoma.

OBJECTIVE: The role of Xenotropic and polytropic retrovirus receptor 1 (XPR1), a cell surface receptor for certain types of murine leukemia viruses, in human cancers has been rarely studied. We aimed to evaluate the values of XPR1 as a biomarker and therapeutic target in head and neck squamous cell carcinoma (HNSCC). METHODS: Bioinformatics tools and online databases, including R packages, ONCOMINE, The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), UALCAN, MethSurv, cBioPortal, and TIMER2.0 were applied in this study. RESULTS: The mRNA and protein expression of XPR1 is significantly up-regulated in HNSCC tissues compared with normal tissues. The receiver operating characteristic (ROC) curve shows XPR1 has high specificity and accuracy in the diagnosis of HNSCC (AUC = 0.883). Patients with high-level expression of XPR1 have poorer overall survival (OS, P = 0.002), disease-specific survival (DSS, P = 0.014), and progress-free interval (PFI, P = 0.017). UALCAN analysis indicates that the methylation of XPR1 promoter in HNSCC is significantly down-regulated. MethSurve was used to investigate the impact of individual CpG islands on the prognosis of HNSCC patients. Low DNA methylation levels of cg11538848 and cg20948051 and high DNA methylation levels of cg23675362, cg18440470, and cg22026687 are significantly related to poor prognosis. The Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicate that XPR1 is involved in various important biological functions and signaling pathways closely related to cancer. The co-expression analysis of XPR1 and N6-methyladenosine (m6A) RNA methylation regulators shows that XPR1 is significantly related to the expression of main m6A regulators. Immune infiltration analysis shows that the expression of XPR1 is related to certain types of immune infiltrating cells and has a positive correlation with the expression of four immune checkpoint genes, PDCD1LG2, CD274, HAVCR2, and SIGLEC15. CONCLUSION: In summary, these results indicate that XPR1 is a potential diagnostic and prognostic biomarker and immunotherapy target for HNSCC. This study sheds new light on understanding the formation and development of HNSCC and sets the basis for further studying the role of XPR1 in HNSCC and other types of cancers.

The Pathology of Primary Familial Brain Calcification: Implications for Treatment.

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.

The Pathology of Primary Familial Brain Calcification: Implications for Treatment / 神经科学通报·英文版

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.

Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer.

Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

The miR-4732-5p/XPR1 axis suppresses the invasion, metastasis, and epithelial-mesenchymal transition of lung adenocarcinoma via the PI3K/Akt/GSK3ß/Snail pathway.

The roles of microRNAs (miRNAs) in the occurrence, metastasis, and prognosis of lung adenocarcinoma (LUAD) have been drawing extensive attention from researchers. The aim of this study is to identify the effects of miR-4732-5p on the migration, invasion, and metastasis of LUAD. In this study, we found that the expression of miR-4732-5p was decreased in LUAD based on the data derived from The Cancer Genome Atlas (TCGA) database, tissues, and cell lines. LUAD patients with a low expression of miR-4732-5p exhibited a lower survival rate. Meanwhile, miR-4732-5p could directly target xenotropic and polytropic retrovirus receptor 1 (XPR1), and elevated XPR1 was observed in LUAD mRNA microarrays, Gene Expression Omnibus (GEO), and The Human Protein Atlas (HPA) database. Overexpression of miR-4732-5p significantly inhibits the migration, invasion, and metastasis of LUAD in vitro and in vivo, which can be reversed by overexpression of XPR1. We also found that the PI3K/Akt/GSK3ß/Snail pathway induced by EGF induced EMT could be inhibited by miR-4732-5p overexpression and XPR1 knockdown. The migration and invasion of LUAD could be converted by cytoskeletal rearrangements, and the polymerization of EGF induced F-actin in A549 cells could be inhibited by elevated miR-4732-5p. Our results suggest that miR-4732-5p exerts anti-tumor effects on the invasion and metastasis of LUAD by regulating XPR1 in vivo and in vitro, indicating that the miR-4732-5p/XPR1 axis may be a potential target for LUAD therapeutic intervention.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors.

The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1, and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1, and the otherwise variable E-MLV envelopes, is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions, with receptor critical sites in envelope, under positive selection but with little variation in envelope and XPR1 in mice carrying P-ERVs. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive, spatial and temporal, co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication.

The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals.

Circulating phosphate levels are tightly controlled within a narrow range in mammals. By using a novel small-molecule inhibitor, we show that the enzymatic activity of inositol hexakisphosphate kinases (IP6K) is essential for phosphate regulation in vivo. IP6K inhibition suppressed XPR1, a phosphate exporter, thereby decreasing cellular phosphate export, which resulted in increased intracellular ATP levels. The in vivo inhibition of IP6K decreased plasma phosphate levels without inhibiting gut intake or kidney reuptake of phosphate, demonstrating a pivotal role of IP6K-regulated cellular phosphate export on circulating phosphate levels. IP6K inhibition-induced decrease in intracellular inositol pyrophosphate, an enzymatic product of IP6K, was correlated with phosphate changes. Chronic IP6K inhibition alleviated hyperphosphataemia, increased kidney ATP, and improved kidney functions in chronic kidney disease rats. Our results demonstrate that the enzymatic activity of IP6K regulates circulating phosphate and intracellular ATP and suggest that IP6K inhibition is a potential novel treatment strategy against hyperphosphataemia.

Clinical implication of xenotropic and polytropic retrovirus receptor 1 in papillary thyroid carcinoma.

To investigate the expression of xenotropic and polytropic retrovirus receptor 1 （） in papillary thyroid cancer （PTC） and its clinical implication. The HPA and UALCAN databases were used to explore the expression of XPR1 in PTC and normal tissues. The cBioPortal database was used to obtain the clinical data of PTC patients and gene expression profile. The correlation of expression with gender，age，sub-types，T stage，N stage，M stage and clinical stage of patients were analyzed. Cox regression was conducted to analysis the factors affecting the prognosis of PTC patients. The mutation of was assessed through cBioPortal database. GO and KEGG analyses were used to explore the related biological pathway of involved in PTC. HPA database analysis showed that XPR1 was highly expressed in PTC tissue compared with normal tissues. UALCAN analysis displayed that expression was significantly higher in PTC tissue compared with normal tissues （<0.01），and the highest and lowest expressions of were observed in tall cell and follicular sub-type of PTC，respectively. The expression of was correlated with age，sub-types，T stage，N stage and disease stage of PTC patients （<0.05 or <0.01），but was not correlated with gender and M stage （all >0.05）. Cox regression analysis showed that was an independent prognostic factor of PTC patients （=2.894，<0.05）. The cBioPortal database indicated that the mutation appeared in 6% PTC patients; the mutation type mainly was missense and the mutation point was located at the E615K. Enrichment analysis indicated that might affect the PTC progression through involvement in metabolic pathway. is highly expressed in PTC tissues，which is associated with the prognosis of patients. Metabolic pathway associated with might play an important role in PTC progression，indicating that might be a novel biomarker for diagnosis and treatment of PTC.

VEGF Mediates Retinal Müller Cell Viability and Neuroprotection through BDNF in Diabetes.

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood-retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities.

Human induced pluripotent stem cells generated from a patient with idiopathic basal ganglia calcification.

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC.

JAM2: A New Culprit at the Pathophysiology of Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is an uncommon degenerative neurological disease that can be hereditary or sporadic, and manifests equally in both sexes and at any age. Several studies initially identified variants in four different genes as the cause of the disorder, all with an autosomal dominant inheritance pattern: SLC20A2, PDGFRB, PDGFB and XPR1. However, there have been reports of the involvement of additional genes in the autosomal recessive inheritance pattern, such as MYORG and more recently JAM2, suggesting that the deregulation of the neurovascular unit (NVU) is important in the pathogenesis of PFBC. The recent study by Schottlaender and collaborators (2020) has added new data to foster these analyses and to enable a better understanding of this underdiagnosed and intriguing neuropsychiatric condition. A great challenge now is to design a model that explains how different pathways might lead to similar neuroimaging findings but with variable clinical outcome, and with marked severity in cases linked to MYORG and JAM2. Currently available databases of detailed gene expression in different vascular cell types from the mouse brain could be used to explore a possible integrative model.

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.

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.

Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions.

BACKGROUND: Mutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family. MATERIALS AND METHODS: We identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations. RESULTS: The patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common. CONCLUSIONS: This is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.

Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate.

Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.