Human hypertension caused by mutations in WNK kinases

被引:1141
作者
Wilson, FH
Disse-Nicodème, S
Choate, KA
Ishikawa, K
Nelson-Willams, C
Desitter, I
Gunel, M
Milford, DV
Lipkin, GW
Achard, JM
Feely, MP
Dussol, B
Berland, Y
Unwin, RJ
Mayan, H
Simon, DB
Farfel, Z
Jeunemaitre, X
Lifton, RP
机构
[1] Yale Univ, Sch Med, Boyer Ctr Mol Med, Howard Hughes Med Inst, New Haven, CT 06510 USA
[2] Coll France, INSERM, U36, F-75005 Paris, France
[3] Birmingham Childrens Hosp, Dept Nephrol, Birmingham B4 6NH, W Midlands, England
[4] Queen Elizabeth Hosp, Dept Nephrol, Birmingham B15 2TT, W Midlands, England
[5] Hop Amiens Sud, Serv Nephrol, Amiens, France
[6] Gen Infirm, Unit Mol Vasc Med, Leeds LS1 3EX, W Yorkshire, England
[7] Hop St Marguerite, Serv Nephrol & Hemodialyse, Marseille, France
[8] UCL, Dept Nephrol, London W1W 7EY, England
[9] UCL, Dept Physiol, London W1W 7EY, England
[10] Tel Aviv Univ, Sheba Med Ctr, Fac Med, Dept Med E, IL-52621 Tel Hashomer, Israel
[11] Tel Aviv Univ, Sheba Med Ctr, Fac Med, Biochem Pharmacol Lab, IL-52621 Tel Hashomer, Israel
关键词
D O I
10.1126/science.1062844
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
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 anti hypertensive drugs.
引用
收藏
页码:1107 / 1112
页数:6
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