Alternative titles; symbols
HGNC Approved Gene Symbol: SLC20A2
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38) : 8:42,416,475-42,541,954 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p11.21 | Basal ganglia calcification, idiopathic, 1 | 213600 | Autosomal dominant | 3 |
The SLC20A2 gene encodes an inorganic phosphate transporter that belongs to the type III sodium-dependent phosphate transporter family (see SLC20A1, 137570). These genes show broad expression in a variety of tissues and likely play a housekeeping role in cellular phosphate uptake (summary by Wang et al., 2012).
The host range of retroviruses is determined primarily by the presence of specific receptors on target cells that are recognized by retroviral envelope glycoproteins. Kaelbling et al. (1991) described a receptor for the gibbon ape leukemia retrovirus. In an effort to isolate related human genes, van Zeijl et al. (1993, 1994) screened a human cDNA library at low stringency using GLVR1 (137570) as a probe. A single GLVR1-related cDNA, designated GLVR2, was isolated. The deduced 652-amino acid GLVR2 protein contains 10 predicted transmembrane domains and shares 62% identity with GLVR1.
Using human-Chinese hamster somatic cell hybrids and a retroviral vector, Garcia et al. (1991) mapped the receptor for the amphotropic murine leukemia virus to the pericentromeric region of human chromosome 8.
Using a somatic cell hybrid panel, van Zeijl et al. (1994) mapped the GLVR2 gene to human chromosome 8, a location distinct from that for GLVR1, which maps to human chromosome 2. The location of GLVR2 on chromosome 8 highlighted the possibility that the locus may encode a receptor for the murine amphotropic virus because a receptor gene (MLVAR) for this virus was mapped to chromosome 8 by Garcia et al. (1991).
Gross (2016) mapped the SLC20A2 gene to chromosome 8p11.21 based on an alignment of the SLC20A2 sequence (GenBank BC028600) with the genomic sequence (GRCh38).
Van Zeijl et al. (1994) found that expression of human GLVR2 in CHO-K1 cells, which are resistant to infection by amphotropic virus because they lack a receptor, rendered the cells sensitive to infection by the virus. Thus, the authors concluded that GLVR2 is a receptor for amphotropic virus. Van Zeijl et al. (1994) pointed out that expression of the GLVR2 protein might be a requirement for infection of human cells by amphotropic retroviral vectors for purposes of gene therapy.
By expression in Xenopus oocytes and rat fibroblasts, Kavanaugh et al. (1994) identified rat Slc20a2, which they called Ram1, as a sodium-dependent phosphate symporter. Voltage-clamp analysis showed net cation influx, suggesting that phosphate is transported with excess sodium ions.
Using RT-PCR analysis, Inden et al. (2016) showed that SLC20A1 and SLC20A2 were widely expressed throughout mouse and human brain, with highest expression in cerebellum. In cerebellum, SLC20A1 and SLC20A2 colocalized in neurons, astrocytes, and vascular endothelial cells.
In affected members of 7 families with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified 7 different heterozygous mutations in the SLC20A2 gene (see, e.g., 158378.0001-158378.0005) that segregated with the disorder. Three families were of Chinese origin, 3 of Spanish origin, and 1 was Brazilian. In vitro functional expression studies in Xenopus oocytes showed that all the missense mutations resulted in substantially impaired transport of inorganic phosphate. However, expression of 2 mutant missense proteins with wildtype SLC20A2 did not result in diminished transport activity, suggesting haploinsufficiency as a pathogenic mechanism. Wang et al. (2012) postulated that functional loss of SLC20A2 in the brain may result in regional accumulation of inorganic phosphate in the extracellular matrix, causing calcium phosphate deposition. No genotype/phenotype correlations were observed.
In 13 (41%) of 29 families with IBGC, Hsu et al. (2013) identified 13 different heterozygous mutations in the SLC20A2 gene (see, e.g., 158378.0003 and 158378.0006-158378.0008). Variants predicted to be deleterious cosegregated with the disease in 5 families. No carriers of SLC20A2 variants were unaffected, suggesting 100% sensitivity of the clinical or CT evaluation. In contrast, several individuals in 3 large families who received an affected disease status based upon clinical examination or CT scan did not carry mutations. Hsu et al. (2013) noted that CT calcifications may be found in up to 1% of the general population, and that a wide range of neuropsychiatric manifestations can be considered part of the disorder. The findings established SLC20A2 as a key gene for familial IBGC.
In an Italian family with IBGC, originally reported by Volpato et al. (2008), Grutz et al. (2016) identified heterozygosity for a large deletion in the SLC20A2 gene (158378.0009). Volpato et al. (2008) had excluded linkage of the disorder in this family to chromosome 14 and Volpato et al. (2009) had erroneously mapped it to 2q37; the locus had previously been designated IBGC2.
In affected members of the 5-generation Chinese family with idiopathic basal ganglia calcification-1 (IBGC1; 213600) originally reported by Dai et al. (2010), Wang et al. (2012) identified a heterozygous 1492G-A transition in the SLC20A2 gene, resulting in a gly498-to-arg (G498R) substitution in a highly conserved residue in transmembrane domain VIII. The mutation was not found in 508 Chinese controls, in the 1000 Genomes Project database, or in 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate. In this family, 9 individuals had idiopathic basal ganglia calcification, but only 4 had clinical symptoms of headache, 1 also with depression; 5 were asymptomatic. Brain imaging of the 36-year-old proband showed symmetric calcium deposition in the caudate nucleus, lentiform nucleus, globus pallidus, inferior part of thalamus, and occipitalis lobes. All were adults, except for 1 asymptomatic 9-year-old boy, who had calcifications only in the globus pallidus.
In affected members of a 4-generation Chinese family with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified a heterozygous 1802C-G transversion in the SLC20A2 gene, resulting in a ser601-to-trp (S601W) substitution in a highly conserved residue in transmembrane domain XI. The mutation was not found in 508 Chinese controls, the 1000 Genomes Project, or 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate. However, expression of the mutant protein with wildtype SLC20A2 did not result in diminished transport activity. Five patients were clinically asymptomatic and 1 had parkinsonism and cerebral infarction at age 73 years. Brain imaging showed calcium deposition primarily limited to the basal ganglia and inferior part of the thalamus. However, 2 affected sisters had a much more severe disorder, with early-onset epilepsy, developmental delay, and mental retardation. Brain imaging of these 2 girls showed marked symmetric calcium deposition in the basal ganglia, inferior part of the thalamus, cerebellum, frontal, temporal, and occipital cortices, and subcortex. These 2 girls were found to carry a heterozygous S601W mutation inherited from their affected father, as well as a ser121-to-cys (S121C) substitution in the SLC20A2 gene inherited from their unaffected mother. The S121C substitution was not found in 508 Chinese controls, but did not show a significant impairment of SLC20A2 transport activity. Thus, its contribution to the severe phenotype lacked clearly supportive evidence.
In 2 affected members of a Chinese family with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified a heterozygous 1802C-T transition in the SLC20A2 gene, resulting in a ser601-to-leu (S601L) substitution in a highly conserved residue in transmembrane domain XI. The mutation was not found in 508 Chinese controls, the 1000 Genomes Project, or in 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate.
Hsu et al. (2013) identified a heterozygous S601L substitution in the SLC20A2 gene in a patient (family F23) with IBGC1 who was of Ashkenazi Jewish and Russian descent.
In 2 affected members of a Spanish family with idiopathic basal ganglia calcification-1 (IBCG1; 213600), Wang et al. (2012) identified a heterozygous 1723G-A transition in the SLC20A2 gene, resulting in a glu575-to-lys (E575K) substitution in a highly conserved residue in transmembrane domain X. The mutation was not found in 288 Spanish controls, the 1000 Genomes Project, or in 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate. However, expression of the mutant protein with wildtype SLC20A2 did not result in diminished transport activity.
In a Spanish patient with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified a heterozygous 1784C-T transition in the SLC20A2 gene, resulting in a thr595-to-met (T595M) substitution in a highly conserved residue in transmembrane domain XI. The mutation was not found in 288 Spanish controls, the 1000 Genomes Project, or 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate.
In 9 affected members of a large multigenerational family (F1) with idiopathic basal ganglia calcification-1 (IBGC1; 213600), originally reported by Geschwind et al. (1999), Hsu et al. (2013) identified a heterozygous 1-bp deletion (c.508delC) in exon 4 of the SLC20A2 gene, resulting in a frameshift and premature termination (Leu170Ter). The family was previously reported to show linkage to a locus on chromosome 14q13, but Hsu et al. (2013) demonstrated that the mutation responsible for the phenotype was in the SLC20A2 gene on chromosome 8p. Two individuals who were clinically affected and were part of the original linkage study were found not to carry the mutation, which may have contributed to the previous erroneous linkage results. The variant was not present in the dbSNP, NHLBI Exome Variant Server, or 1000 Genomes Project databases.
In 9 affected members of a family (F2) with idiopathic basal ganglia calcification-1 (IBGC1; 213600), originally reported by Brodaty et al. (2002), Hsu et al. (2013) identified a heterozygous 4-bp deletion (c.1828_1831delTCCC) in exon 11 of the SLC20A2 gene, resulting in a frameshift and premature termination (Ser610AlafsTer17). The variant was not present in the dbSNP, NHLBI Exome Variant Server, or 1000 Genomes Project databases. One clinically affected family member did not carry the mutation.
In 8 affected members of a family (F5) of Irish-English descent with idiopathic basal ganglia calcification-1 (IBGC1; 213600), previously reported by Manyam et al. (2001) and Oliveira et al. (2004), Hsu et al. (2013) identified a heterozygous 2-bp deletion (c.583_584GT) in exon 5 of the SLC20A2 gene, resulting in a frameshift and premature termination (Val195LeufsTer61). The variant was not present in the dbSNP, NHLBI Exome Variant Server, or 1000 Genomes databases. Two clinically affected family members did not carry the mutation.
In affected members of an Italian family with idiopathic basal ganglia calcification-1 (IBGC1; 213600), originally reported by Volpato et al. (2008), Grutz et al. (2016) identified heterozygosity for a large deletion encompassing exons 6 to 10 in the SLC20A2 gene. The mutation, c.(613+1_614-1)_(1794+1_1795-1)del, was predicted to result in a frameshift (Val205GlyfsTer65).
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