title: Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
abstract: Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (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 BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin 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 mutations, 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.
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Boyden
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Nelson-Williams
authors.forename: Anita
authors.initials: A
authors.lastname: Farhi
authors.forename: Hakan R
authors.initials: HR
authors.lastname: Toka
authors.forename: Irina R
authors.initials: IR
authors.lastname: Tikhonova
authors.forename: Robert
authors.initials: R
authors.lastname: Bjornson
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Giacomo
authors.initials: G
authors.lastname: Colussi
authors.forename: Marcel
authors.initials: M
authors.lastname: Lebel
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gordon
authors.forename: Ben A
authors.initials: BA
authors.lastname: Semmekrot
authors.forename: Alain
authors.initials: A
authors.lastname: Poujol
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Välimäki
authors.forename: Maria E
authors.initials: ME
authors.lastname: De Ferrari
authors.forename: Sami A
authors.initials: SA
authors.lastname: Sanjad
authors.forename: Michael
authors.initials: M
authors.lastname: Gutkin
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Karet
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Tucci
authors.forename: Jim R
authors.initials: JR
authors.lastname: Stockigt
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keppler-Noreuil
authors.forename: Craig C
authors.initials: CC
authors.lastname: Porter
authors.forename: Sudhir K
authors.initials: SK
authors.lastname: Anand
authors.forename: Margo L
authors.initials: ML
authors.lastname: Whiteford
authors.forename: Ira D
authors.initials: ID
authors.lastname: Davis
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Dewar
authors.forename: Alberto
authors.initials: A
authors.lastname: Bettinelli
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Fadrowski
authors.forename: Craig W
authors.initials: CW
authors.lastname: Belsha
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Hunley
authors.forename: Raoul D
authors.initials: RD
authors.lastname: Nelson
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.forename: Trevor R P
authors.initials: TR
authors.lastname: Cole
authors.forename: Maury
authors.initials: M
authors.lastname: Pinsk
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Mohan
authors.initials: M
authors.lastname: Shenoy
authors.forename: Priya
authors.initials: P
authors.lastname: Vaidyanathan
authors.forename: John W
authors.initials: JW
authors.lastname: Foreman
authors.forename: Majid
authors.initials: M
authors.lastname: Rasoulpour
authors.forename: Farook
authors.initials: F
authors.lastname: Thameem
authors.forename: Hania Z
authors.initials: HZ
authors.lastname: Al-Shahrouri
authors.forename: Jai
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Goilav
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D015331:Cohort Studies; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics*; D004573:Electrolytes; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005799:Genes, Dominant / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D012965:Sodium Chloride / Q000378:metabolism; D014883:Water-Electrolyte Imbalance / Q000150:complications / Q000235:genetics* / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D004573:Electrolytes; C489837:KLHL3 protein, human; D008840:Microfilament Proteins; D012965:Sodium Chloride; D011188:Potassium