ORPHA: 244305; DO: 0080077;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q35.3 | Nephrolithiasis/osteoporosis, hypophosphatemic, 1 | 612286 | Autosomal dominant | 3 | SLC34A1 | 182309 |
A number sign (#) is used with this entry because hypophosphatemic nephrolithiasis/osteoporosis-1 (NPHLOP1) is caused by heterozygous mutation in the SLC34A1 gene (182309) on chromosome 5q35.
See also NPHLOP2 (612287), caused by mutation in the SLC9A3R1 gene (604990).
Prie et al. (2002) reported 2 unrelated patients with hypophosphatemia and decreased renal phosphate absorption. The first patient was a 34-year-old man with recurrent urolithiasis. His maximal renal phosphate resorption, normalized for GFR, was decreased at 0.47 mmol/L. The second patient was a 64-year-old woman with bone demineralization. Her only daughter had a spinal deformity and a history of arm fractures. Both mother and daughter had decreased renal phosphate absorption at 0.58 and 0.67 mmol/L, respectively.
In 2 of 20 unrelated probands with hypophosphatemic nephrolithiasis/osteoporosis, Prie et al. (2002) identified 2 different heterozygous mutations in the SLC34A1 gene (182309.0001 and 182309.0002). The study provided genetic evidence that heterozygous mutations in the SLC34A1 gene 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.
By targeted mutagenesis, Beck et al. (1998) generated mice deficient in the Npt2 (Slc34a1) 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.
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]
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]