Abstract
Gordon syndrome is a rare inherited monogenic form of hypertension, which is associated with hyperkalaemia and metabolic acidosis. Since the recognition of this predominantly autosomal dominant condition in the 1960s, the study of families with Gordon syndrome has revealed four genes WNK1, WNK4, KLHL3, and CUL3 to be implicated in its pathogenesis after a phenotype–genotype correlation was realised. The encoded proteins Kelch-like 3 and Cullin 3 interact to form a ring-like complex to ubiquitinate WNK-kinase 4, which, in normal circumstances, interacts with the sodium chloride co-symporter (NCC), the epithelial sodium channel (ENaC), and the renal outer medullary potassium channel (ROMK) in an inhibitory manner to maintain normokalaemia and normotension. WNK-kinase 1 has an inhibitory action on WNK-kinase 4. Mutations in WNK1, WNK4, KLHL3, and CUL3 all result in the accumulation of WNK-kinase 4 and subsequent hypertension, hyperkalaemia, and metabolic acidosis. This review explains the clinical aspects, disease mechanisms, and molecular genetics of Gordon syndrome.
Highlights
Gordon syndrome, otherwise known as Pseudohypoaldosteronism type 2 or familial hyperkalaemia and hypertension syndrome, is a rare inherited form of low-renin hypertension associated with hyperkalaemia and metabolic acidosis [1,2,3,4]
This review will describe the clinical presentations and disease mechanisms of known genes implicated in this condition, WNK1, WNK4, KLHL3, and CUL3
Pendrin-mediated cellular Cl− /HCO3− exchange and number of Pendrin-expressing cells significantly increase and genetic ablation of Pendrin completely corrects metabolic acidosis in TgWnk4PHA2 mice. This suggests that metabolic acidosis is, likely to be caused by distal nephron bicarbonate wasting in Gordon syndrome [63]
Summary
WNK4 mutations (PHA2B) were subsequently identified in Gordon syndrome patients These exonic missense mutations occurred within a unique amino acid sequence, ‘the acidic motif’ of WNK4, and resulted in charge-changing substitutions but did not affect the kinase activity of WNK4. This ‘acidic motif’ has only made sense since the discovery that the WNKs bind to Kelch-like 3 through the acidic motif [12,13]. This review will describe the clinical presentations and disease mechanisms of known genes implicated in this condition, WNK1, WNK4, KLHL3, and CUL3
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