Alternative titles; symbols
HGNC Approved Gene Symbol: XPR1
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38) : 1:180,632,022-180,890,279 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Basal ganglia calcification, idiopathic, 6 | 616413 | Autosomal dominant | 3 |
The XPR1 gene encodes a receptor for xenotropic and polytropic murine viruses (Tailor et al., 1999). There are 4 classes of murine leukemia virus (MLV): xenotropic (X), ecotropic (E), amphotropic (A), and polytropic (P). X- and E-MLV cannot exogenously infect mouse cells and are inherited as part of the mouse genome. While X-MLV can infect other mammalian species but not cells from laboratory mice, A- (see SLC20A2; 158378) and P-MLV can infect mouse and other species. See Levy (1999) for a review of MLVs.
By cloning a human T-lymphocyte cDNA library into a retroviral vector, transducing the library into naturally X-MLV-resistant mouse fibroblasts, and PCR amplification, Tailor et al. (1999) isolated a cDNA encoding XPR1. Expression of XPR1 in mouse and hamster MLV-resistant fibroblasts rendered the cells susceptible to both X- and P-MLV. The deduced 696-amino acid XPR1 protein contains 8 or 9 potential membrane-spanning regions, 7 potential N-glycosylation sites, and 7 dileucines that may stimulate endocytosis via clathrin-coated pits. Northern blot analysis detected a 4.5-kb XPR1 transcript in all tissues tested, with highest expression in pancreas, kidney, placenta, hematopoietic tissues, and heart, and lowest expression in skeletal muscle. Expression of XPR1 was greater in fetal liver than adult liver. A 9.5-kb XPR1 transcript was also detected in all tissues tested except liver and bone marrow.
Using methods similar to those of Tailor et al. (1999), Battini et al. (1999) isolated a cDNA encoding XPR1. Sequence analysis predicted that XPR1, which shares 25% amino acid identity with the yeast Syg1 protein, contains a 236-amino acid, hydrophilic N-terminal region that precedes the 8 hydrophobic domains.
By radiation hybrid analysis, Battini et al. (1999) mapped the XPR1 gene to 1q25.1, flanked by the AT3 (107300) and LAMC1 (150290) genes. Yang et al. (1999) and Tailor et al. (1999) mapped the mouse Xpr1 gene, also called Rmc1, to chromosome 1.
The XPR1 protein mediates phosphate export, suggesting that it has a role in phosphate homeostasis (summary by Legati et al., 2015).
In 9 affected members of a large family of Swedish origin with idiopathic basal ganglia calcification-6 (IBGC6; 616413), originally reported by Boller et al. (1977), Legati et al. (2015) identified a heterozygous missense mutation in the XPR1 gene (L145P; 605237.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Further sequencing of XPR1 in 86 patients with a similar disorder identified heterozygous pathogenic missense mutations in 5 patients from 4 unrelated families (605237.0002-605237.0004). In vitro functional expression studies showed that all the mutations impaired phosphate efflux to various degrees. Legati et al. (2015) postulated that inhibition of phosphate export would lead to increased intracellular phosphate concentration and intracellular calcium/phosphate precipitation.
In affected members of a large family of Swedish origin with idiopathic basal ganglia calcification-6 (IBGC6; 616413), originally reported by Boller et al. (1977), Legati et al. (2015) identified a heterozygous c.434T-C transition (c.434T-C, NM_004736.3) in the XPR1 gene, resulting in a leu145-to-pro (L145P) substitution at a highly conserved residue in the SPX domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases, or in 287 in-house control exomes. Further sequencing of XPR1 in 86 cases with a similar disorder identified the same L145P variant in 2 affected individuals from a French family. Patient cells showed impaired phosphate efflux compared to controls, and in vitro functional expression studies showed that the mutant protein was unable to reestablish phosphate efflux or serve as a receptor for the X-MLV during infection in XPR1-null cells. Flow cytometry indicated that the mutation affected cell surface exposure of XPR1 with retention of the mutant protein in the cell, although expression levels of the mutant protein were normal. The mutation also showed a dominant-negative effect, interfering with phosphate efflux of endogenous XPR1.
In a man with idiopathic basal ganglia calcification-6 (IBGC6; 616413), Legati et al. (2015) identified a heterozygous c.407G-A transition (c.407G-A, NM_004736.3) in the XPR1 gene, resulting in a ser136-to-asn (S136N) substitution at a conserved residue in the SPX domain. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases, or in 287 in-house control exomes. In vitro studies showed that the mutant protein was present at the plasma membrane and served as a retroviral receptor, but phosphate efflux was impaired.
In a man with idiopathic basal ganglia calcification-6 (IBGC6; 616413), Legati et al. (2015) identified a heterozygous c.419T-C transition (c.419T-C, NM_004736.3) in the XPR1 gene, resulting in a leu140-to-pro (L140P) substitution at a conserved residue in the SPX domain. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases, or in 287 in-house control exomes. In vitro studies showed that the mutant protein was present at the plasma membrane and served as a retroviral receptor, but phosphate efflux was impaired.
In a woman with idiopathic basal ganglia calcification-6 (IBGC6; 616413), Legati et al. (2015) identified a heterozygous c.653T-C transition (c.653T-C, NM_004736.3) in the XPR1 gene, resulting in a leu218-to-ser (L218S) substitution at a conserved residue near the SPX domain. The patient's deceased mother was reportedly affected, but DNA was not available. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases, or in 287 in-house control exomes. In vitro studies showed that the mutant protein was present at the plasma membrane and served as a retroviral receptor, but phosphate efflux was impaired.
Battini, J.-L., Rasko, J. E. J., Miller, A. D. A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. Proc. Nat. Acad. Sci. 96: 1385-1390, 1999. [PubMed: 9990033] [Full Text: https://doi.org/10.1073/pnas.96.4.1385]
Boller, F., Boller, M., Gilbert, J. Familial idiopathic cerebral calcifications. J. Neurol. Neurosurg. Psychiat. 40: 280-285, 1977. [PubMed: 886353] [Full Text: https://doi.org/10.1136/jnnp.40.3.280]
Legati, A., Giovannini, D., Nicolas, G., Lopez-Sanchez, U., Quintans, B., Oliveira, J. R. M., Sears, R. L., Ramos, E. M., Spiteri, E., Sobrido, M.-J., Carracedo, A., Castro-Fernandez, C., and 29 others. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nature Genet. 47: 579-581, 2015. [PubMed: 25938945] [Full Text: https://doi.org/10.1038/ng.3289]
Levy, J. A. Xenotropism: the elusive viral receptor finally uncovered. Proc. Nat. Acad. Sci. 96: 802-804, 1999. [PubMed: 9927648] [Full Text: https://doi.org/10.1073/pnas.96.3.802]
Tailor, C. S., Nouri, A., Lee, C. G., Kozak, C., Kabat, D. Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc. Nat. Acad. Sci. 96: 927-932, 1999. [PubMed: 9927670] [Full Text: https://doi.org/10.1073/pnas.96.3.927]
Yang, Y.-L., Guo, L., Xu, S., Holland, C. A., Kitamura, T., Hunter, K., Cunningham, J. M. Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmc1. Nature Genet. 21: 216-219, 1999. [PubMed: 9988277] [Full Text: https://doi.org/10.1038/6005]