Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities

Boyden, Lynn M., Choi, Murim, Choate, Keith A., Nelson-Williams, Carol J., Farhi, Anita, Toka, Hakan R., Tikhonova, Irina R., Bjornson, Robert, Mane, Shrikant M., Colussi, Giacomo, Lebel, Marcel, Gordon, Richard D., Semmekrot, BA, Poujol, Alain, Valimaki, Matti J., De Ferrari, Maria E., Sanjad, Sami A., Gutkin, Michael, Karet, Fiona E., Tucci, JR, Stockigt, Jim R., Keppler-Noreuil, Kim M., Porter, Craig C., Anand, Sudhir K., Whiteford, Margo L., Davis, Ira D., Dewar, Stephanie B., Bettinelli, Alberto, Fadrowski, Jeff J., Belsha, Craig W., Hunley, Tracy E., Nelson, Raoul D., Trachtman, Howard, Cole, Trevor R. P., Pinsk, Maury, Bockenhauer, Detlef, Shenoy, Mohan, Vaidyanathan, Priya, Foreman, John W., Rasoulpour, Majid, Thameem, Farook, Al-Shahrouri, Hania Z., Radhakrishnan, Jai, Gharavi, Ali G., Goilav, Beatrice and Lifton, Richard P. (2012) Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature, 482 7383: 98-103. doi:10.1038/nature10814

Author Boyden, Lynn M.
Choi, Murim
Choate, Keith A.
Nelson-Williams, Carol J.
Farhi, Anita
Toka, Hakan R.
Tikhonova, Irina R.
Bjornson, Robert
Mane, Shrikant M.
Colussi, Giacomo
Lebel, Marcel
Gordon, Richard D.
Semmekrot, BA
Poujol, Alain
Valimaki, Matti J.
De Ferrari, Maria E.
Sanjad, Sami A.
Gutkin, Michael
Karet, Fiona E.
Tucci, JR
Stockigt, Jim R.
Keppler-Noreuil, Kim M.
Porter, Craig C.
Anand, Sudhir K.
Whiteford, Margo L.
Davis, Ira D.
Dewar, Stephanie B.
Bettinelli, Alberto
Fadrowski, Jeff J.
Belsha, Craig W.
Hunley, Tracy E.
Nelson, Raoul D.
Trachtman, Howard
Cole, Trevor R. P.
Pinsk, Maury
Bockenhauer, Detlef
Shenoy, Mohan
Vaidyanathan, Priya
Foreman, John W.
Rasoulpour, Majid
Thameem, Farook
Al-Shahrouri, Hania Z.
Radhakrishnan, Jai
Gharavi, Ali G.
Goilav, Beatrice
Lifton, Richard P.
Title Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
Publication date 2012-02
Sub-type Article (original research)
DOI 10.1038/nature10814
Volume 482
Issue 7383
Start page 98
End page 103
Total pages 6
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2013
Language eng
Formatted abstract
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndromefeaturing hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal
salt reabsorption and K+ and H+ excretion1. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTBdomain-containing kelch proteins such as KLHL3 are components of cullin–RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains2–8. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate9 and cullin5 binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3  substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na–Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are  expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3  utations, increased Na–Cl reabsorption, and disease pathogenesis. These findings  demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K+ and pH homeostasis.
Keyword WNK Kinases
K+ Channel
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
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