Gordon Syndrome: a continuing story.

Gordon Syndrome (GS) is a rare familial hypertension syndrome with a characteristic hyperkalaemia which distinguishes it from other syndromic forms of hypertension that typically cause hypokalaemia. Patients with GS respond to aggressive salt-restriction or relatively small doses of thiazide diuretics, which suggests that activation of the thiazide-sensitive Na/Cl cotransporter (NCC) in the distal nephron is to blame. However, the mechanism has proved to be complex. In 2001, mutations in genes encoding two serine/threonine kinases, WNK1 and WNK4, were identified as causing GS. However, it took several years to appreciate that these kinases operated in a cascade with downstream serine/threonine kinases (SPAK and OSR1) actually phosphorylating and activating NCC and the closely related cotransporters NKCC1 and NKCC2. The hyperkalaemia in GS arises from an independent action of WNK1/WNK4 to reduce cell-surface expression of ROMK, the secretory K-channel in the collecting ducts. However, mutations in WNK1/4 are present in a small minority of GS families, and further genes have emerged (CUL3 and KLHL3) that code for Cullin-3 (a scaffold protein in an ubiquitin-E3 ligase) and an adaptor protein, Kelch3, respectively. These new players regulate the ubiquitination and proteasomal degradation of WNK kinases, thereby adding to the complex picture we now have of NCC regulation in the distal nephron.