title: Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.
abstract: 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.
authors: Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. brian@lexgen.com
authors: Brian P
authors: BP
authors: Zambrowicz
authors: Alejandro
authors: A
authors: Abuin
authors: Ramiro
authors: R
authors: Ramirez-Solis
authors: Lizabeth J
authors: LJ
authors: Richter
authors: James
authors: J
authors: Piggott
authors: Hector
authors: H
authors: BeltrandelRio
authors: Eric C
authors: EC
authors: Buxton
authors: Joel
authors: J
authors: Edwards
authors: Rick A
authors: RA
authors: Finch
authors: Carl J
authors: CJ
authors: Friddle
authors: Anupma
authors: A
authors: Gupta
authors: Gwenn
authors: G
authors: Hansen
authors: Yi
authors: Y
authors: Hu
authors: Wenhu
authors: W
authors: Huang
authors: Crystal
authors: C
authors: Jaing
authors: Billie Wayne
authors: BW
authors: Key
authors: Peter
authors: P
authors: Kipp
authors: Buckley
authors: B
authors: Kohlhauff
authors: Zhi-Qing
authors: ZQ
authors: Ma
authors: Diane
authors: D
authors: Markesich
authors: Robert
authors: R
authors: Payne
authors: David G
authors: DG
authors: Potter
authors: Ny
authors: N
authors: Qian
authors: Joseph
authors: J
authors: Shaw
authors: Jeff
authors: J
authors: Schrick
authors: Zheng-Zheng
authors: ZZ
authors: Shi
authors: Mary Jean
authors: MJ
authors: Sparks
authors: Isaac
authors: I
authors: Van Sligtenhorst
authors: Peter
authors: P
authors: Vogel
authors: Wade
authors: W
authors: Walke
authors: Nianhua
authors: N
authors: Xu
authors: Qichao
authors: Q
authors: Zhu
authors: Christophe
authors: C
authors: Person
authors: Arthur T
authors: AT
authors: Sands
mesh_terms: D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D015723:Gene Library; D005821:Genetic Techniques; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000628:therapy; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000379:methods; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016324:Sequence Tagged Sites; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse