Severe Arterial Hypertension from Cullin 3 Mutations Is Caused by Both Renal and Vascular Effects

Mutations in four genes, WNK lysine deficient protein kinase 1 and 4 ( WNK1 and WNK4 ), kelch like family member 3 ( KLHL3 ), or Cullin 3 ( CUL3 ), can result in familial hyperkalemic hypertension (FHHt), a rare Mendelian form of human arterial hypertension. Although all mutations result in an increased abundance of WNK1 or WNK4, all FHHt-causing CUL3 mutations, resulting in the skipping of exon 9, lead to a more severe phenotype.