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CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin\u2010RING\u2010ubiquitin\u2010ligase complexes. Bound to KLHL3, CUL3\u2010RBX1 ubiquitylates WNK kinases, promoting their ubiquitin\u2010mediated proteasomal degradation. Since WNK kinases activate Na\/Cl co\u2010transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin\u2010RING\u2010ligase formation. We report here that the PHA2E mutant, CUL3\n                    <jats:sup>\u0394403\u2013459<\/jats:sup>\n                    , is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3\n                    <jats:sup>\u0394403\u2013459<\/jats:sup>\n                    auto\u2010ubiquitylates and loses interaction with two important Cullin regulators: the COP9\u2010signalosome and CAND1. A novel knock\u2010in mouse model of CUL3\n                    <jats:sup>WT<\/jats:sup>\n                    <jats:sup>\/\u0394403\u2013459<\/jats:sup>\n                    closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201505444","type":"journal-article","created":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T23:09:23Z","timestamp":1439939363000},"page":"1285-1306","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Characterisation of the Cullin\u20103 mutation that causes a severe form of familial hypertension and hyperkalaemia"],"prefix":"10.1038","volume":"7","author":[{"given":"Frances\u2010Rose","family":"Schumacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Siew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E","family":"Cleary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raya S","family":"Al Maskari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T","family":"Ferryman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Hardege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Yasmin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichola L","family":"Figg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radoslav","family":"Enchev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Knebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M","family":"O'Shaughnessy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thimo","family":"Kurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,18]]},"reference":[{"key":"BFEMMM201505444_CR1","first-page":"257","volume":"19","author":"N Akhtar","year":"2009","unstructured":"Akhtar N, Hafeez F (2009) A rare case of Gitelman's syndrome with hypophosphatemia. 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