Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension

Mohammed Z. Ferdaus, James A. McCormick

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Autosomal dominant mutations in cullin-3 (Cul3) cause the most severe form of familial hyperkalemic hypertension (FHHt). Cul3 mutations cause skipping of exon 9, which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-Δ9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the cullin-RING ubiquitin ligase family that mediates ubiquitination and thus degradation of cellular proteins, including with-no-lysine [K] kinases (WNKs). In CUL3-Δ9-mediated FHHt, proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets sterile 20/SPS-1 related proline/alanine-rich kinase and oxidative stressresponse kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na+-Cl- cotransporter. Several groups have suggested different mechanisms by which CUL3-Δ9 causes FHHt. The majority of these are derived from in vitro data, but recently the Kurz group (Schumacher FR, Siew K, Zhang J, Johnson C, Wood N, Cleary SE, Al Maskari RS, Ferryman JT, Hardege I, Figg NL, Enchev R, Knebel A, O’Shaughnessy KM, Kurz T. EMBO Mol Med 7: 1285-1306, 2015) described the first mouse model of CUL3-Δ9-mediated FHHt. Analysis of this model suggested that CUL3-Δ9 is degraded in vivo, and thus Cul3 mutations cause FHHt by inducing haploinsufficiency. We recently directly tested this model but found that other dominant effects of CUL3-Δ9 must contribute to the development of FHHt. In this review, we focus on our current knowledge of CUL3-Δ9 action gained from in vitro and in vivo models that may help unravel this complex problem.

Original languageEnglish (US)
Pages (from-to)F915-F920
JournalAmerican Journal of Physiology - Renal Physiology
Issue number5
StatePublished - 2018


  • Cullin-3
  • Distal nephron
  • Familial hyperkalemic hypertension
  • Kinases
  • Potassium
  • Sodium transport

ASJC Scopus subject areas

  • Physiology
  • Urology


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