Hypophosphatemia nephrolithiasis osteoporosis type 2 (NPHLOP2)

(OMIM phenotype number #612287)

Hypophosphatemia nephrolithiasis osteoporosis type 2 (NPHLOP2) is caused by heterozygous mutation in the SLC9A3R1 or NHERF1 gene. NHERF1, the sodium-hydrogen exchanger regulatory factor 1,  binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. NHERF1 mutations cause decreased renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. Impaired renal phosphate reabsorption (measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR)), increases the risks of nephrolithiasis and bone demineralization.

Gene

SLC9A3R1 gene, 17q25.1 (OMIM gene/locus number #604990)

Phenotype

Kidney stones, nephocalcinosis, osteoporosis.

Main biochemical alterations

High Ur P, low Pi, low renal TmP/GFR, normal calcium, high Ur Ca, low/normal PTH, normal 25 OH D, high 1,25(OH)2D, high bone ALP, normal Ca, and normal intact FGF23.

References

  1. Karim Z, Gérard B, Bakouh N, et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35.
  2. Courbebaisse M, Leroy C, Bakouh N et al. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One. 2012;7(4):e34764.
  3. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  4. http://www.omim.org