Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

By L. Boyden, Murim Choi, K. Choate, C. Nelson-Williams, Anita Farhi, Hakan R Toka, Irina R. Tikhonova, R. Bjornson, Shrikant M. Mane, G. Colussi and 36 more. Nature, 2012

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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.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2069dc3a8b7f91901aebe58bd33b378052d8f605

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Citations in the corpus

De novo mutations in histone modifying genes in congenital heart disease (2013, neutral): “112, 698–706 (2013). 2.”
A survey of tools for variant analysis of next-generation genome sequencing data (2013, background): “Whole-genome and whole-exome sequencing have been successfully utilized to identify the genes responsible for complex hereditary diseases [39, 40], where whole-genome sequencing enables testing of both mentioned hypotheses.”
The integrated landscape of driver genomic alterations in glioblastoma (2013, background): “Notably, the concentration of LZTR1 mutations in the kelch domain reflects a similar pattern of mutations in the kelch-coding region of KLHL3 , which was recently identified in families with hypertension and electrolytic abnormalities 30,31 .”