Alternative titles; symbols
HGNC Approved Gene Symbol: SLC34A1
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:177,384,434-177,398,848 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.3 | ?Fanconi renotubular syndrome 2 | 613388 | Autosomal recessive | 3 |
| Hypercalcemia, infantile, 2 | 616963 | Autosomal recessive | 3 | |
| Nephrolithiasis/osteoporosis, hypophosphatemic, 1 | 612286 | Autosomal dominant | 3 |
Magagnin et al. (1993) cloned from human kidney cortex a cDNA encoding a renal proximal tubular, brush-border membrane Na(+)-phosphate cotransporter referred to as NaPi3. Hartmann et al. (1996) reported the cloning and characterization of the mouse (Npt2) and human (NPT2) genes. The genes were cloned by screening mouse genomic and human chromosome 5-specific libraries, respectively.
Hartmann et al. (1996) determined that the mouse and human NPT2 genes are approximately 16 kb and contain 13 exons. Putative CAAT and TATA boxes were located, respectively, at positions -147 and -40 of the Npt2 gene and -143 and -51 of the NPT2 gene, relative to nucleotide 1 of the corresponding cDNAs. The translation initiation site was within exon 2 of both genes.
Kos et al. (1994) used PCR analysis of somatic cell hybrids and FISH to map the NPT2 gene to 5q35. Ghishan et al. (1994) used the same 2 methods plus Southern blotting of somatic cell hybrids to map the gene to 5q but determined its regional location to be 5q13 rather than 5q35. McPherson et al. (1997) resolved this discrepancy using 3 independent methods. Results using a human chromosome 5/rodent somatic cell hybrid deletion panel, FISH with a PAC clone containing the NPT2 locus, and analysis of a chromosome 5-specific radiation hybrid panel were all consistent with the 5q35 assignment of the NPT2 gene. The radiation hybrid placed NPT2 between polymorphic microsatellite markers D5S498 and D5S469. Kos et al. (1996) used FISH to map the NPT2 gene to rabbit chromosome 3. Zhang et al. (1997) mapped Slc17a2, the homologous mouse gene, to chromosome band 13B.
Prie et al. (2002) coinjected Xenopus oocytes with wildtype and mutant NPT2 RNA. The results indicated that the mutant NPT2 protein had altered function and that NPT2 plays a major part in phosphate homeostasis.
Hypophosphatemic Nephrolithiasis/Osteoporosis 1
Prie et al. (2002) studied 20 patients with urolithiasis or osteoporosis and persistent idiopathic hypophosphatemia associated with a decrease in maximal renal phosphate resorption (612286). Two of the patients were found to have mutations in the NPT2 gene: one, with recurrent hypophosphatemic urolithiasis, had an ala48-to-phe (A48P; 182309.0001) mutation; the other, with hypophosphatemic osteoporosis, had a val147-to-met (V147M; 182309.0002) mutation. The mutations were not found in 120 subjects with normal maximal renal phosphate resorption, normalized according to the glomerular filtration rate. The study provided genetic evidence that heterozygous mutations of NPT2 are involved in hypophosphatemia resulting from idiopathic renal phosphate loss and that a defect in renal phosphate resorption contributes to the pathogenesis of urolithiasis and bone demineralization.
Fanconi Renotubular Syndrome 2
In an affected brother and sister from a consanguineous Arab family with Fanconi renotubular syndrome mapping to chromosome 5q35.1-q35.3 (FRTS2; 613388), originally reported by Tieder et al. (1988), Magen et al. (2010) analyzed the candidate gene SLC34A1 and identified homozygosity for an in-frame 21-bp duplication (182309.0003). Analysis in Xenopus oocytes expressing mutant SLC34A1 demonstrated complete loss of function in the homozygous state.
Infantile Hypercalcemia 2
In 16 patients from 15 families with infantile hypercalcemia-2 (HCINF2; 616963), Schlingmann et al. (2016) identified biallelic mutations in the SLC34A1 gene (see, e.g., 182309.0004-182309.0009).
Tenenhouse et al. (1994) studied the defect in renal Na(+)-Pi cotransport in brush border membranes of Hyp mice, an apparently authentic model for X-linked hypophosphatemia (307800) in the human. The reduction in cotransport could be ascribed to a proportionate decrease in the abundance of cotransporter mRNA and protein. Since the gene is on chromosome 5 rather than the X chromosome, the primary defect in this disorder cannot lie in NPT2. Physiologic studies using parabiosis and renal transplantation demonstrate that the renal defect in brush border membrane sodium-dependent phosphate transport in Hyp mice is not intrinsic to the kidney but rather depends on a circulating humoral factor, which is not parathyroid hormone, for its expression. Thus, the product of the gene on the X chromosome may be a regulator of the NPT2 gene located on chromosome 5.
By targeted mutagenesis, Beck et al. (1998) generated mice deficient in the Npt2 gene. They found that homozygous mutants (Npt2 -/-) exhibited increased urinary P(i) excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. The biochemical features were typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH; 241530), a mendelian disorder of renal P(i) resorption. However, unlike HHRH patients, Npt2 -/- mice did not have rickets or osteomalacia. At weaning, Npt2 -/- mice had poorly developed trabecular bones and retarded secondary ossification, but with increasing age there was a dramatic reversal and eventual overcompensation of the skeletal phenotype. The findings demonstrated that Npt2 is a major regulator of P(i) homeostasis and is necessary for normal skeletal development.
In a 34-year-old man with recurrent nephrolithiasis, hypophosphatemia, and reduced renal phosphate resorption (NPHLOP1; 612286), Prie et al. (2002) found heterozygosity for 2 nucleotide substitutions in adjacent positions of the SLC34A1 (formerly SLC17A2) gene: 223G-T and 224C-T. Sequencing of cloned PCR products established that these substitutions were located on the same allele in exon 3, resulting in an ala48-to-phe (A48F) substitution. In vitro functional expression studies in Xenopus oocytes showed that the mutant protein resulted in lower phosphate current, decreased affinity for phosphate, and decreased phosphate uptake compared to wildtype, and also showed a dominant-negative effect.
In a 64-year-old woman with idiopathic bone demineralization, hypophosphatemia, and reduced renal phosphate resorption (NPHLOP1; 612286), Prie et al. (2002) found heterozygosity for a G-to-A transition of nucleotide 520 in exon 5 of the SLC34A1 (formerly SLC17A2) gene, resulting in a val147-to-met (V147M) substitution. Her only daughter, who also had the mutation, had a spinal deformity and a history of arm fractures, with hypophosphatemia and low maximal renal phosphate reabsorption. In vitro functional expression studies in Xenopus oocytes showed that the mutant protein resulted in lower phosphate current, decreased affinity for phosphate, and decreased phosphate uptake compared to wildtype, and also showed a dominant-negative effect.
In an affected brother and sister from a consanguineous Arab family with Fanconi renotubular syndrome mapping to chromosome 5q35.1-q35.3 (FRTS2; 613388), originally reported by Tieder et al. (1988), Magen et al. (2010) identified homozygosity for an in-frame 21-bp duplication (2061dup21) in exon 5 of the SLC34A1 gene, resulting in duplication of 7 amino acids at positions 154 to 160, immediately adjacent to a highly conserved 5-residue motif. The unaffected mother and an unaffected brother were heterozygous for the duplication, which was not found in 100 ethnically matched controls. Measurement of phosphate-induced currents in Xenopus oocytes expressing wildtype and mutant SLC34A1 demonstrated complete loss of function in the homozygous state. The amplitude of currents produced by oocytes expressing both wildtype and mutant was similar to that of oocytes expressing wildtype alone, ruling out a dominant-negative effect. Tagging studies using enhanced green fluorescent protein in transfected opossum kidney cells showed that unlike the wildtype protein, which localizes to the plasma membrane, the mutant protein accumulated in the cytoplasm.
In 2 cousins from a consanguineous Turkish family with infantile hypercalcemia-2 (HCINF2; 616963), Schlingmann et al. (2016) identified homozygosity for a splice site mutation (c.644+1G-A, NM_003052) in intron 6 of the SLC34A1 gene. Their unaffected parents were each heterozygous for the mutation, which was not found in at least 204 Caucasian control alleles.
In a 6-year-old Turkish girl with infantile hypercalcemia-2 (HCINF2; 616963), Schlingmann et al. (2016) identified homozygosity for a c.458G-T transversion (c.458G-T, NM_003052) in exon 4 of the SLC34A1 gene, resulting in a gly153-to-val (G153V) substitution. Her unaffected parents were heterozygous for the mutation. The G153V mutation was also identified in compound heterozygosity with a W488R substitution in an unrelated 1-year-old Turkish boy with infantile hypercalcemia. Neither missense mutation was found in at least 204 Caucasian control alleles. Functional analysis in Xenopus oocytes showed that wildtype protein induced significant uptake of labeled phosphate, whereas neither the G153V or W488R mutant induced uptake significantly different from that of noninjected control cells. Transiently transfected opossum kidney cells showed complete intracellular retention of both mutant proteins with no detectable actin colocalization, in contrast to wildtype, which localized at the plasma membrane and colocalized with actin.
In a 2-year-old Turkish girl with infantile hypercalcemia-2 (HCINF2; 616963), Schlingmann et al. (2016) identified homozygosity for a splice site mutation (c.1006+1G-A, NM_003052) in intron 9 of the SLC34A1 gene. Her unaffected parents were heterozygous for the mutation, which was not found in at least 204 Caucasian control alleles.
In a 14-year-old Dutch girl (patient F4.1) with infantile hypercalcemia-2 (HCINF2; 616963), originally reported as patient 3 by Lameris et al. (2010), Schlingmann et al. (2016) identified compound heterozygosity for 2 missense mutations: the first was a c.458G-C transversion (c.458G-C, NM_003052) in exon 4, resulting in a gly153-to-ala (G153A) substitution, and the second was a c.1006T-G transversion in exon 9, resulting in a cys336-to-gly (C336G; 182309.0008) substitution. The G153A mutation was also identified in compound heterozygosity with a splice site mutation and a V408E substitution, respectively, in a 3-year-old Polish girl and a 1-year-old German boy with infantile hypercalcemia. The mutations were detected in heterozygosity in the Polish and German parents, and none of them were found in at least 204 Caucasian control alleles. Schlingmann et al. (2016) noted that although most heterozygous carriers of SLC34A1 mutations had no renal pathology, the German boy's mother underwent nephrectomy in adolescence after recurrent pyelonephritis and a staghorn calculus. Functional analysis in Xenopus oocytes showed that wildtype protein induced significant uptake of labeled phosphate, whereas none of the missense mutants induced uptake significantly different from that of noninjected control cells. Transient transfection experiments with the missense mutations in opossum kidney cells showed complete intracellular retention of the mutant proteins with no detectable actin colocalization, in contrast to wildtype, which localized at the plasma membrane and colocalized with actin.
For discussion of the c.1006T-G transversion (c.1006T-G, NM_003052) in exon 9 of the SLC34A1 gene, resulting in a cys336-to-gly (C336G) substitution, that was found in compound heterozygous state in a patient with infantile hypercalcemia-2 (HCINF2; 616963) by Schlingmann et al. (2016), see 182309.0007.
In a 3.5-year-old Polish girl with polyuria who was discovered to have nephrocalcinosis and high-normal serum calcium at age 18 months (HCINF2; 616963), Schlingmann et al. (2016) identified homozygosity for a 21-bp deletion (c.271_291del, NM_003052) in exon 4 of the SLC34A1 gene, resulting in the in-frame deletion of 7 amino acids (91del7). The deletion was found in heterozygosity in her unaffected parents, and was also present in the Exome Variant Server with an allele frequency of approximately 2.6% in the European American population; testing of a larger sample yielded an allele frequency of approximately 1.6% (8 of 512 alleles). The deletion was also detected in compound heterozygosity in 3 additional unrelated patients with infantile hypercalcemia: the second allele carried an L155P, W305X, or V408E mutation, respectively, in a 17-year-old Polish boy, a 3-year-old German girl, and a 6-year-old Belgian girl. Functional analysis in Xenopus oocytes showed that wildtype protein induced significant uptake of labeled phosphate, and the 91del7 mutant induced uptake comparable to wildtype. Both missense mutants did not induce uptake that was significantly different from that of noninjected control cells. In transiently transfected opossum kidney cells, the 91del7 mutant was found to be expressed both in intracellular compartments as well as at the plasma membrane, indicating partial retention of this variant inside the cell; however, both missense mutants showed complete intracellular retention of the mutant proteins with no detectable actin colocalization, in contrast to wildtype, which localized at the plasma membrane and colocalized with actin.
Beck, L., Karaplis, A. C., Amizuka, N., Hewson, A. S., Ozawa, H., Tenenhouse, H. S. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Nat. Acad. Sci. 95: 5372-5377, 1998. [PubMed: 9560283] [Full Text: https://doi.org/10.1073/pnas.95.9.5372]
Ghishan, F. K., Knobel, S., Dasuki, M., Butler, M., Phillips, J. Chromosomal localization of the human renal sodium phosphate transporter to chromosome 5: implications for X-linked hypophosphatemia. Pediat. Res. 35: 510-513, 1994. [PubMed: 8047391]
Hartmann, C. M., Hewson, A. S., Kos, C. H., Hilfiker, H., Soumounou, Y., Murer, H., Tenenhouse, H. S. Structure of murine and human renal type II Na(+)-phosphate cotransporter genes (Npt2 and NPT2). Proc. Nat. Acad. Sci. 93: 7409-7414, 1996. [PubMed: 8693007] [Full Text: https://doi.org/10.1073/pnas.93.14.7409]
Kos, C. H., Tihy, F., Econs, M. J., Murer, H., Lemieux, N., Tenenhouse, H. S. Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35. Genomics 19: 176-177, 1994. [PubMed: 8188224] [Full Text: https://doi.org/10.1006/geno.1994.1034]
Kos, C. H., Tihy, F., Murer, H., Lemieux, N., Tenenhouse, H. S. Comparative mapping of Na(+)-phosphate cotransporter genes, NPT1 and NPT2, in human and rabbit. Cytogenet. Cell Genet. 75: 22-24, 1996. [PubMed: 8995482] [Full Text: https://doi.org/10.1159/000134449]
Lameris, A. L. L., Huybers, S., Burke, J. R., Monnens, L. A., Bindels, R. J. M., Hoenderop, J. G. J. Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis? Nephrol. Dial. Transplant. 25: 3504-3509, 2010. [PubMed: 20466674] [Full Text: https://doi.org/10.1093/ndt/gfq221]
Magagnin, S., Werner, A., Markovich, D., Sorribas, V., Stange, G., Biber, J., Murer, H. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc. Nat. Acad. Sci. 90: 5979-5983, 1993. [PubMed: 8327470] [Full Text: https://doi.org/10.1073/pnas.90.13.5979]
Magen, D., Berger, L., Coady, M. J., Ilivitzki, A., Militianu, D., Tieder, M., Selig, S., Lapointe, J. Y., Zelikovic, I., Skorecki, K. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. New Eng. J. Med. 362: 1102-1109, 2010. [PubMed: 20335586] [Full Text: https://doi.org/10.1056/NEJMoa0905647]
McPherson, J. D., Krane, M. C., Wagner-McPherson, C. B., Kos, C. H., Tenenhouse, H. S. High resolution mapping of the renal sodium-phosphate cotransporter gene (NPT2) confirms its localization to human chromosome 5q35. Pediat. Res. 41: 632-634, 1997. [PubMed: 9128283] [Full Text: https://doi.org/10.1203/00006450-199705000-00005]
Prie, D., Huart, V., Bakouh, N., Planelles, G., Dellis, O., Gerard, B., Hulin, P., Benque-Blanchet, F., Silve, C., Grandchamp, B., Friedlander, G. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. New Eng. J. Med. 347: 983-991, 2002. [PubMed: 12324554] [Full Text: https://doi.org/10.1056/NEJMoa020028]
Schlingmann, K. P., Ruminska, J., Kaufmann, M., Dursun, I., Patti, M., Kranz, B., Pronicka, E., Ciara, E., Akcay, T., Bulus, D., Cornelissen, E. A. M., Gawlik, A., and 16 others. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J. Am. Soc. Nephrol. 27: 604-614, 2016. [PubMed: 26047794] [Full Text: https://doi.org/10.1681/ASN.2014101025]
Tenenhouse, H. S., Werner, A., Biber, J., Ma, S., Martel, J., Roy, S., Murer, H. Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets: molecular characterization. J. Clin. Invest. 93: 671-676, 1994. [PubMed: 8113402] [Full Text: https://doi.org/10.1172/JCI117019]
Tieder, M., Arie, R., Modai, D., Samuel, R., Weissgarten, J., Liberman, U. A. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi's syndrome. New Eng. J. Med. 319: 845-849, 1988. [PubMed: 2842681] [Full Text: https://doi.org/10.1056/NEJM198809293191307]
Zhang, X.-X., Tenenhouse, H. S., Hewson, A. S., Murer, H., Eydoux, P. Assignment of renal-specific Na(+)-phosphate cotransporter gene Slc17a2 to mouse chromosome band 13B by in situ hybridization. Cytogenet. Cell Genet. 77: 304-305, 1997. [PubMed: 9284943] [Full Text: https://doi.org/10.1159/000134603]