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Author Notes:

E-mail: dominique.prie@inserm.fr

Conceived and designed the experiments: DP GF BG GP RAH.

Performed the experiments: MC NB CS RAH CL LB DP.

Analyzed the data: DP BG GF RAH GP MC.

Contributed reagents/materials/analysis tools: CL CS LB BG DP RAH.

Wrote the paper: DP.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This study was supported by grants from Inserm, Université Paris Descartes, Assistance Publique – Hôpitaux de Paris, Agence Nationale de la Recherche (grant N°ANR-07-PHYSIO_017_01) and Association Laboratoire de Recherches Physiologiques.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • OPOSSUM KIDNEY-CELLS
  • PARATHYROID-HORMONE
  • PROXIMAL TUBULE
  • PDZ PROTEINS
  • COTRANSPORTER
  • IIA
  • MOUSE
  • MICE
  • NEPHROLITHIASIS
  • ISOFORMS

A New Human NHERF1 Mutation Decreases Renal Phosphate Transporter NPT2a Expression by a PTH-Independent Mechanism

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 7, Number 4

Publisher:

, Pages e34764-e34764

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1) binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. Methods: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. Results: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A) located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. Conclusions: Our results indicate that the PDZ1 domain is critical for NHERF1- NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms.

Copyright information:

© 2012 Courbebaisse et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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