en
Scientific article
Letter
English

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

Published inNature genetics, vol. 44, no. 4, p. 456-460,S1-3
Publication date2012
Abstract

Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.

Keywords
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Base Sequence
  • Blood Pressure/genetics
  • Carrier Proteins/genetics
  • Child
  • Female
  • Humans
  • Ion Transport/genetics
  • Kidney/metabolism
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Nephrons/metabolism
  • Polymorphism, Single Nucleotide
  • Pseudohypoaldosteronism/genetics/metabolism/physiopathology
  • Sequence Analysis, DNA
  • Signal Transduction
  • Sodium Chloride Symporters/genetics/metabolism
  • Young Adult
Citation (ISO format)
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. In: Nature genetics, 2012, vol. 44, n° 4, p. 456–460,S1–3. doi: 10.1038/ng.2218
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Article (Published version)
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Identifiers
ISSN of the journal1061-4036
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