NHERF1Mutations and Responsiveness of Renal Parathyroid Hormone

Abstract

Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from animal models suggest that sodium-hydrogen exchanger regulatory factor 1 (NHERF1) controls renal phosphate transport. We sequenced the NHERF1 gene in 158 patients, 94 of whom had either nephrolithiasis or bone demineralization. We identified three distinct mutations in seven patients with a low TmP/GFR value. No patients with normal TmP/GFR values had mutations. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. These NHERF1 mutations suggest a previously unrecognized cause of renal phosphate loss in humans.

Dynamic Na+-H+ Exchanger Regulatory Factor-1 Association and Dissociation Regulate Parathyroid Hormone Receptor Trafficking at Membrane Microdomains

“…This interaction and the tethering of NHERF1 to the actin cytoskeleton through the ezrin-binding domain forms a complex that stabilizes the PTHR at the cell membrane, thereby delaying endocytosis and desensitization (15)(16)(17). NHERF1-null mice (18) and patients (19) harboring NHERF1 polymorphisms or coding region mutations display mineral ion wasting and a bone phenotype, consistent with an important biological role of NHERF1/PTHR interactions. Upon activation by PTH, the PTHR recruits ␤-arrestins, traffics to clathrin, and is endocytosed in early endosomes and eventually recycled to the membrane or targeted for degradation (20 -22).…”

“…Here, we show that NHERF1 establishes dynamic interactions with the PTHR within membrane microdomains, suggesting that NHERF1 promotes the recruitment of specific signaling proteins in a temporally and spatially coordinated manner at different steps of receptor activation and internalization. We chose the PTHR as a model to characterize the fate of NHERF1 because the phenotype of NHERF1-null mice (18) and humans bearing NHERF1 polymorphisms or mutations (19) involves renal mineral ion wasting, osteopenia, and osteomalacia, suggesting that PTHR interactions with NHERF1 modulate vital physiological functions.…”

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

“…The monogenic causes of NL/NC reported in the literature are very heterogeneous (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). This heterogeneity is evident in our cohort, in which causative mutations were distributed among 14 of the 30 genes screened.…”

Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) Directly Regulates Osteogenesis

“…1). To avoid potentially confounding effects of renal phosphate wasting on bone (11,14), mice were fed a phosphate-rich diet. In this setting, bone formation rate was dramatically reduced in NHERF1-null mice under conditions where serum phosphorous, calcium, and PTH were normal (Fig.…”

“…Mice deficient in NHERF1 exhibit prominent renal phosphate wasting and skeletal abnormalities (11), as do patients harboring NHERF1 mutations (14). In both cases the bone pathology, which is characterized by severe osteomalacia with accumulation of nonmineralized osteoid, was interpreted as a secondary consequence of hypophosphatemia.…”