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Open AccessReview

The Molecular Genetics of Gordon Syndrome

by Holly Mabillard 1 and John A. Sayer 1,2,3,*
1
Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK
2
Translational and Clinical Research Institute, Faculty of Medical Sciences, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
3
NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
*
Author to whom correspondence should be addressed.
Genes 2019, 10(12), 986; https://doi.org/10.3390/genes10120986
Received: 22 October 2019 / Revised: 22 November 2019 / Accepted: 25 November 2019 / Published: 29 November 2019
(This article belongs to the Special Issue Genetics of Tubulopathies)
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.
Keywords: Gordon syndrome; tubulopathy; genetics; WNK1; WNK4; KLHL3; CUL3 Gordon syndrome; tubulopathy; genetics; WNK1; WNK4; KLHL3; CUL3
MDPI and ACS Style

Mabillard, H.; Sayer, J.A. The Molecular Genetics of Gordon Syndrome. Genes 2019, 10, 986.

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