Human hypertension caused by mutations in WNK kinases

FH Wilson; S Disse-Nicodeme; KA Choate; K Ishikawa; C Nelson-Williams; I Desitter; M Gunel; David Milford; Graham Lipkin; JM Achard; MP Feely; B Dussol; Y Berland; RJ Unwin; H Mavan; DB Simon; Z Farfel; X Jeunemaitre; RP Lifton

doi:10.1126/science.1062844

Human hypertension caused by mutations in WNK kinases

FH Wilson, S Disse-Nicodeme, KA Choate, K Ishikawa, C Nelson-Williams, I Desitter, M Gunel, David Milford, Graham Lipkin, JM Achard, MP Feely, B Dussol, Y Berland, RJ Unwin, H Mavan, DB Simon, Z Farfel, X Jeunemaitre, RP Lifton

Birmingham Medical School

Research output: Contribution to journal › Article

1110 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1107-1112
Number of pages	6
Journal	Science
Volume	293
DOIs	https://doi.org/10.1126/science.1062844
Publication status	Published - 10 Aug 2001

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Wilson, FH., Disse-Nicodeme, S., Choate, KA., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D., Lipkin, G., Achard, JM., Feely, MP., Dussol, B., Berland, Y., Unwin, RJ., Mavan, H., Simon, DB., Farfel, Z., Jeunemaitre, X., & Lifton, RP. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1107-1112. https://doi.org/10.1126/science.1062844

@article{e91d6437e3b949c8b7f4273147e639e6,

title = "Human hypertension caused by mutations in WNK kinases",

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.",

author = "FH Wilson and S Disse-Nicodeme and KA Choate and K Ishikawa and C Nelson-Williams and I Desitter and M Gunel and David Milford and Graham Lipkin and JM Achard and MP Feely and B Dussol and Y Berland and RJ Unwin and H Mavan and DB Simon and Z Farfel and X Jeunemaitre and RP Lifton",

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doi = "10.1126/science.1062844",

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Wilson, FH, Disse-Nicodeme, S, Choate, KA, Ishikawa, K, Nelson-Williams, C, Desitter, I, Gunel, M, Milford, D, Lipkin, G, Achard, JM, Feely, MP, Dussol, B, Berland, Y, Unwin, RJ, Mavan, H, Simon, DB, Farfel, Z, Jeunemaitre, X & Lifton, RP 2001, 'Human hypertension caused by mutations in WNK kinases', Science, vol. 293, pp. 1107-1112. https://doi.org/10.1126/science.1062844

TY - JOUR

T1 - Human hypertension caused by mutations in WNK kinases

AU - Wilson, FH

AU - Disse-Nicodeme, S

AU - Choate, KA

AU - Ishikawa, K

AU - Nelson-Williams, C

AU - Desitter, I

AU - Gunel, M

AU - Milford, David

AU - Lipkin, Graham

AU - Achard, JM

AU - Feely, MP

AU - Dussol, B

AU - Berland, Y

AU - Unwin, RJ

AU - Mavan, H

AU - Simon, DB

AU - Farfel, Z

AU - Jeunemaitre, X

AU - Lifton, RP

PY - 2001/8/10

Y1 - 2001/8/10

N2 - 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.

AB - 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.

U2 - 10.1126/science.1062844

DO - 10.1126/science.1062844

M3 - Article

C2 - 11498583

SN - 1095-9203

VL - 293

SP - 1107

EP - 1112

JO - Science

JF - Science

ER -

Human hypertension caused by mutations in WNK kinases

Abstract

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