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

DOI Web Site 被引用文献12件
  • Brian P. Zambrowicz
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Alejandro Abuin
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Ramiro Ramirez-Solis
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Lizabeth J. Richter
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • James Piggott
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Hector BeltrandelRio
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Eric C. Buxton
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Joel Edwards
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Rick A. Finch
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Carl J. Friddle
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Anupma Gupta
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Gwenn Hansen
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Yi Hu
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Wenhu Huang
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Crystal Jaing
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Billie Wayne Key
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Peter Kipp
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Buckley Kohlhauff
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Zhi-Qing Ma
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Diane Markesich
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Robert Payne
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • David G. Potter
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Ny Qian
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Joseph Shaw
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Jeff Schrick
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Zheng-Zheng Shi
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Mary Jean Sparks
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Isaac Van Sligtenhorst
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Peter Vogel
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Wade Walke
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Nianhua Xu
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Qichao Zhu
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Christophe Person
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381
  • Arthur T. Sands
    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381

書誌事項

公開日
2003-11-10
DOI
  • 10.1073/pnas.2336103100
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p> 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 ≈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 <jats:italic>Wnk1</jats:italic> kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in <jats:italic>WNK1</jats:italic> 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 <jats:sup>+</jats:sup> and H <jats:sup>+</jats:sup> excretion. Consistent with the human genetic studies, <jats:italic>Wnk1</jats:italic> heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the <jats:italic>Wnk1</jats:italic> mutation died during embryonic development before day 13 of gestation. These results demonstrate that <jats:italic>Wnk1</jats:italic> is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach. </jats:p>

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