1. Human Hypertension Caused by Mutations in WNK Kinases
- Author
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Graham Lipkin, Yvon Berland, Frederick H. Wilson, Murat Gunel, Haim Mayan, Kazuhiko Ishikawa, Morgan P. Feely, Isabelle Desitter, David V. Milford, Keith A. Choate, Zvi Farfel, David B. Simon, Bertrand Dussol, Jean-Michel Achard, Sandra Disse-Nicodeme, Robert J. Unwin, Xavier Jeunemaitre, Richard P. Lifton, and Carol Nelson-Williams
- Subjects
Male ,Cytoplasm ,Genetic Linkage ,Pseudohypoaldosteronism ,Molecular Sequence Data ,Mutation, Missense ,Protein Serine-Threonine Kinases ,Biology ,Gene Expression Regulation, Enzymologic ,Minor Histocompatibility Antigens ,WNK Lysine-Deficient Protein Kinase 1 ,medicine ,Humans ,Amino Acid Sequence ,Kidney Tubules, Collecting ,Pseudohypoaldosteronism Type 2 ,Kidney Tubules, Distal ,Sequence Deletion ,Genetics ,Chromosomes, Human, Pair 12 ,Multidisciplinary ,Base Sequence ,urogenital system ,Kinase ,Intracellular Signaling Peptides and Proteins ,Chromosome Mapping ,Membrane Proteins ,Phosphoproteins ,WNK1 ,medicine.disease ,Introns ,Pedigree ,WNK4 ,Familial hypertension ,Liddle Syndrome ,Intercellular Junctions ,Microscopy, Fluorescence ,Hypertension ,Mutation ,Zonula Occludens-1 Protein ,Female ,Chromosomes, Human, Pair 17 ,Signal Transduction - Abstract
Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K + and H + excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K + , and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
- Published
- 2001