Human hypertension caused by mutations in WNK kinases.
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.
Wilson
F H
FH
Howard Hughes Medical Institute; Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06510 USA.
Disse-Nicodème
S
S
Choate
K A
KA
Ishikawa
K
K
Nelson-Williams
C
C
Desitter
I
I
Gunel
M
M
Milford
D V
DV
Lipkin
G W
GW
Achard
J M
JM
Feely
M P
MP
Dussol
B
B
Berland
Y
Y
Unwin
R J
RJ
Mayan
H
H
Simon
D B
DB
Farfel
Z
Z
Jeunemaitre
X
X
Lifton
R P
RP
D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008040:Genetic Linkage; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D007365:Intercellular Junctions / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D007685:Kidney Tubules, Collecting / Q000201:enzymology / Q000648:ultrastructure; D007686:Kidney Tubules, Distal / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D017384:Sequence Deletion; D015398:Signal Transduction; D000076204:WNK Lysine-Deficient Protein Kinase 1; D062826:Zonula Occludens-1 Protein
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C433806:WNK4 protein, human