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Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

Pubmed ID: 14610273


  • Zambrowicz BP
  • Abuin A
  • Ramirez-Solis R
  • Richter LJ
  • Piggott J
  • BeltrandelRio H
  • Buxton EC
  • Edwards J
  • Finch RA
  • Friddle CJ
  • Gupta A
  • Hansen G
  • Hu Y
  • Huang W
  • Jaing C
  • Key BW
  • Kipp P
  • Kohlhauff B
  • Ma ZQ
  • Markesich D
  • Payne R
  • Potter DG
  • Qian N
  • Shaw J
  • Schrick J
  • Shi ZZ
  • Sparks MJ
  • Van Sligtenhorst I
  • Vogel P
  • Walke W
  • Xu N
  • Zhu Q
  • Person C
  • Sands AT


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 25, 2003

Associated Grants


Mesh Terms

  • Animals
  • Base Sequence
  • Blood Pressure
  • DNA, Complementary
  • Gene Library
  • Genetic Techniques
  • Heterozygote
  • Humans
  • Hypertension
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Sequence Tagged Sites