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Review
. 2019 Nov 29;10(12):986.
doi: 10.3390/genes10120986.

The Molecular Genetics of Gordon Syndrome

Holly Mabillard  1 , John A Sayer  1   2   3
Affiliations
Review

The Molecular Genetics of Gordon Syndrome

Holly Mabillard et al. Genes (Basel). .

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.

Keywords: CUL3; Gordon syndrome; KLHL3; WNK1; WNK4; genetics; tubulopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanisms underlying Gordon syndrome.
Figure 2
Figure 2
Regulation of NCC by WNKs.
Figure 3
Figure 3
Mechanisms of potassium homeostasis in the β-intercalated and principal cells of the collecting duct.
Figure 4
Figure 4
Summary of pathophysiology of Gordon syndrome in a tubular cell representative of different parts of the nephron.
See this image and copyright information in PMC

References

    1. Paver W., Pauline G. Hypertension and hyperpotassaemia without renal disease in a young male. Med. J. Aust. 1964;2:305–306. doi: 10.5694/j.1326-5377.1964.tb115766.x. - DOI - PubMed
    1. Arnold J.E., Healy J.K. Hyperkalemia, hypertension and systemic acidosis without renal failure associated with a tubular defect in potassium excretion. Am. J. Med. 1969;47:461–472. doi: 10.1016/0002-9343(69)90230-7. - DOI - PubMed
    1. Gordon R.D. The syndrome of hypertension and hyperkalemia with normal glomerular filtration rate: Gordon’s syndrome. Aust. N. Z. J. Med. 1986;16:183–184. doi: 10.1111/j.1445-5994.1986.tb01145.x. - DOI - PubMed
    1. Schambelan M., Sebastian A., Rector F.J. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): Role of increased renal chloride reabsorption. Kidney Int. 1981;19:716–727. doi: 10.1038/ki.1981.72. - DOI - PubMed
    1. Toka H.R., Koshy J.M., Hariri A. The molecular basis of blood pressure variation. Pediatr. Nephrol. 2013;28:387–399. doi: 10.1007/s00467-012-2206-9. - DOI - PubMed

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