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

被引：292

作者：

Zambrowicz, BP ^{[1
]}

Abuin, A ^{[1
]}

Ramirez-Solis, R ^{[1
]}

Richter, LJ ^{[1
]}

Piggott, J ^{[1
]}

BeltrandelRio, H ^{[1
]}

Buxton, EC ^{[1
]}

Edwards, J ^{[1
]}

Finch, RA ^{[1
]}

Friddle, CJ ^{[1
]}

Gupta, A ^{[1
]}

Hansen, G ^{[1
]}

Hu, Y ^{[1
]}

Huang, WH ^{[1
]}

Jaing, C ^{[1
]}

Key, BW ^{[1
]}

Kipp, P ^{[1
]}

Kohlhauff, B ^{[1
]}

Ma, ZQ ^{[1
]}

Markesich, D ^{[1
]}

Payne, R ^{[1
]}

Potter, DG ^{[1
]}

Qian, N ^{[1
]}

Shaw, J ^{[1
]}

Schrick, J ^{[1
]}

Shi, ZZ ^{[1
]}

Sparks, MJ ^{[1
]}

Van Sligtenhorst, I ^{[1
]}

Vogel, P ^{[1
]}

Walke, W ^{[1
]}

Xu, NH ^{[1
]}

Zhu, QC ^{[1
]}

Person, C ^{[1
]}

Sands, AT ^{[1
]}

机构：

[1] Lexicon Genet, The Woodlands, TX 77381 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2003年 / 100卷 / 24期

关键词：

D O I：

10.1073/pnas.2336103100

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 approximate to60% 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 11, 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.

引用

页码：14109 / 14114

页数：6

共 28 条

[1] From sequence to phenotype:: Reverse genetics in Drosophila melanogaster [J].