Familial hyperkalemic hypertension (FHHt) is a rare monogenic disease that results from mutations in the kinases WNK1 and WNK4 or mutations in the ubiquitin ligase cullin 3 (CUL3) or the CUL3 substrate adaptor kelch-like 3 (KLHL3). Disease-associated mutations increase WNK kinase activity and thereby enhance activity of the Na-Cl transporter (NCC), which increases blood pressure and potassium levels. In this episode, David Ellison and colleagues reveal that FHHt-associated CUL3 mutant CUL3Δ403-459 exhibits enhanced ubiquitin ligase activity, leading to KLHL3 degradation and a subsequent increase in WNK kinase abundance. Moreover, kidney-specific deletion of Cul3 resulted in renal dysfunction, inflammation, and fibrosis in mice. This study provides insight in to the pathological mechanisms underlying FHHt-causing CUL3 mutations and demonstrates an essential role for CUL3 in the kidney.
Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (
James A. McCormick, Chao-Ling Yang, Chong Zhang, Brittney Davidge, Katharina I. Blankenstein, Andrew S. Terker, Bethzaida Yarbrough, Nicholas P. Meermeier, Hae J. Park, Belinda McCully, Mark West, Aljona Borschewski, Nina Himmerkus, Markus Bleich, Sebastian Bachmann, Kerim Mutig, Eduardo R. Argaiz, Gerardo Gamba, Jeffrey D. Singer, David H. Ellison