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Human Hypertension Caused by Mutations in WNK Kinases
Frederick H. Wilson,1Sandra Disse-Nicodème,2*Keith A. Choate,1*Kazuhiko Ishikawa,1*Carol Nelson-Williams,1Isabelle Desitter,2Murat Gunel,1David V. Milford,3Graham W. Lipkin,4Jean-Michel Achard,5Morgan P. Feely,6Bertrand Dussol,7Yvon Berland,7Robert J. Unwin,8Haim Mayan,9David B. Simon,1Zvi Farfel,9Xavier Jeunemaitre,2Richard P. Lifton1
Hypertension is a major public health problem of largely unknown
cause. Here, we identify two genes causing pseudohypoaldosteronismtype
II, a Mendelian trait featuring hypertension, increased renalsalt
reabsorption, and impaired K+ and H+ excretion.
Both genes encode members of the WNK family of serine-threoninekinases. Disease-causing mutations in WNK1 are large
intronicdeletions that increase WNK1 expression. The
mutations in WNK4are missense, which cluster in a short,
highly conserved segmentof 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
localizesto tight junctions. The WNK kinases and their associated
signalingpathway(s) may offer new targets for the development of
antihypertensivedrugs.
1 Howard Hughes Medical Institute; Yale
University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06510 USA.
2 INSERM
U36, Collège de France. 11, Place Marcellin Berthelot. 75005 Paris, France.
3 Department of Nephrology,
Birmingham Children's Hospital, Birmingham B4 6NH, UK.
4 Department of Nephrology, Queen Elizabeth
Hospital, Birmingham B15 2TH, UK.
5 Service de
Néphrologie, Hopital d'Amiens-Sud, Amiens, France.
6 Unit of Molecular Vascular Medicine, The General
Infirmary, Leeds, UK.
7 Service de
Néphrologie et Hémodialyse, Hopital Sainte Marguerite,
Marseille, France.
8 Departments of Nephrology and
Physiology, University College London, London W1W 7EY, UK.
9 Department of Medicine E' and Laboratory of
Biochemical Pharmacology, Sheba Medical Center, Tel Aviv University
School of Medicine, Tel Hashomer 52621, Israel.
*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail:
richard.lifton{at}yale.edu
The editors suggest the following Related Resources on Science sites:
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280, 35281-35289
|Abstract »|Full Text »|PDF »
WNK1 Activates SGK1 by a Phosphatidylinositol 3-Kinase-dependent and Non-catalytic Mechanism.
B.-e Xu, S. Stippec, A. Lazrak, C.-L. Huang, and M. H. Cobb (2005)
J. Biol. Chem.
280, 34218-34223
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A mathematical model of rat distal convoluted tubule. II. Potassium secretion along the connecting segment.
WNK1 Kinase Polymorphism and Blood Pressure Response to a Thiazide Diuretic.
S. T. Turner, G. L. Schwartz, A. B. Chapman, and E. Boerwinkle (2005)
Hypertension
46, 758-765
|Abstract »|Full Text »|PDF »
Association of Common Variation in the HNF1{alpha} Gene Region With Risk of Type 2 Diabetes.
W. Winckler, N. P. Burtt, J. Holmkvist, C. Cervin, P. I.W. de Bakker, M. Sun, P. Almgren, T. Tuomi, D. Gaudet, T. J. Hudson, et al. (2005)
Diabetes
54, 2336-2342
|Abstract »|Full Text »|PDF »
With-No-Lysine Kinases: The Discovery of a New Pathway in Hypertension Using Human Genetic Studies.
C. Delaloy, J. Hadchouel, and X. Jeunemaitre (2005)
Hypertension
46, 263-264
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A New Kindred With Pseudohypoaldosteronism Type II and a Novel Mutation (564D>H) in the Acidic Motif of the WNK4 Gene.
A. P. Golbang, M. Murthy, A. Hamad, C.-H. Liu, G. Cope, W. Van't Hoff, A. Cuthbert, and K. M. O'Shaughnessy (2005)
Hypertension
46, 295-300
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Properties of WNK1 and Implications for Other Family Members.
L. Y. Lenertz, B.-H. Lee, X. Min, B.-e Xu, K. Wedin, S. Earnest, E. J. Goldsmith, and M. H. Cobb (2005)
J. Biol. Chem.
280, 26653-26658
|Abstract »|Full Text »|PDF »
WNK1 activates SGK1 to regulate the epithelial sodium channel.
B.-e Xu, S. Stippec, P.-Y. Chu, A. Lazrak, X.-J. Li, B.-H. Lee, J. M. English, B. Ortega, C.-L. Huang, and M. H. Cobb (2005)
PNAS
102, 10315-10320
|Abstract »|Full Text »|PDF »
Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.
S. J. Newhouse, C. Wallace, R. Dobson, C. Mein, J. Pembroke, M. Farrall, D. Clayton, M. Brown, N. Samani, A. Dominiczak, et al. (2005)
Hum. Mol. Genet.
14, 1805-1814
|Abstract »|Full Text »|PDF »
Identification of WNK1 as a Substrate of Akt/Protein Kinase B and a Negative Regulator of Insulin-stimulated Mitogenesis in 3T3-L1 Cells.
Z. Y. Jiang, Q. L. Zhou, J. Holik, S. Patel, J. Leszyk, K. Coleman, M. Chouinard, and M. P. Czech (2005)
J. Biol. Chem.
280, 21622-21628
|Abstract »|Full Text »|PDF »
