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A naturally occurring human Nedd4–2 variant displays impaired ENaC regulation in Xenopus laevis oocytes

¹Division of Nephrology and Hypertension, Department of Clinical Research, University of Bern, CH-3010 Bern; ²Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland; and ³Faculty of Medicine X. Bichat, Institut National de la Santé et de la Recherche Médicale Unité 409, 75018 Paris, France

Submitted 6 October 2003 ; accepted in final form 10 May 2004

The epithelial Na⁺ channel (ENaC) is regulated by the ubiquitin-protein ligase Nedd4–2 via interaction with ENaC PY-motifs. These PY-motifs are mutated/deleted in Liddle's syndrome, resulting in elevated Na⁺ reabsorption and hypertension explained partly by impaired ENaC-Nedd4–2 interaction. We hypothesized that Nedd4–2 is a susceptibility gene for hypertension and screened 856 renal patients and healthy controls for mutations in a subset of exons of the human Nedd4–2 gene that are relevant for ENaC regulation by PCR/single-strand conformational polymorphism. Several variants were identified, and one nonsynonymous mutation (Nedd4–2-P355L) was further characterized. This mutation next to the 3' donor site of exon 15 does not affect in vitro splicing of Nedd4–2 mRNA. However, in the Xenopus oocyte expression system, Nedd4–2-P355L-dependent ENaC inhibition was weaker compared with the wild type (Nedd4–2-WT), and this difference depended on the presence of intact PY-motifs on ENaC. This could not be explained by the amount of wild type or mutant Nedd4–2 coimmunoprecipitating with ENaC. When the phosphorylation level of human Nedd4–2 Ser⁴⁴⁸ (known to be phosphorylated by the Sgk1 kinase) was determined with a specific anti-pSer⁴⁴⁸ antibody, we observed stronger basal phosphorylation of Nedd4–2-P355L. Both the phosphorylation level and the accompanying amiloride-sensitive Na⁺ currents could be further enhanced to approximately the same levels by coexpressing Sgk1. In addition, the role of the two other putative Sgk1 phosphorylation sites (S342 and T367) appears also to be affected by the P355L mutation. The differential phosphorylation status between wild-type and mutant Nedd4–2 provides an explanation for the different potential to inhibit ENaC activity.

genetic variation; sodium ion homeostasis; ubiquitination; phosphorylation

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