Association of hypertension with T594M mutation in β subunit of epithelial sodium channels in black people resident in London

Baker, Emma H.; Dong, YB; Sagnella, Giuseppe A.; Rothwell, Michael J.; Onipinla, AK; Markandu, Nirmala D.; Cappuccio, Francesco P.; Cook, Derek G; Persu, Alexandre; Corvol, Pierre; Jeunemaı̂tre, Xavier; Carter, ND; MacGregor, G. A.

doi:10.1016/s0140-6736(97)07306-6

Cited by 236 publications

(130 citation statements)

References 17 publications

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“…While of potential interest, these results remain unconfirmed so far. For the SCNN1B gene a-comparably rare-T594M polymorphism located in the C terminus but unrelated to the crucial PPPXY motif has been identified that was more frequent in hypertensive (∼8% heterozygous carriers) than in normotensive (∼2%) blacks (Baker et al 1998), results that were not reproduced in another black cohort (Nkeh et al 2003;Hollier et al 2006). A similar approach for the SCNN1G subunit resulted in the identification of a promoter polymorphism (G-173A) and a silent polymorphism in exon 3 with allele frequencies of ∼25% each (Persu et al 1999;Iwai et al 2001).…”

Section: Liddle's Syndromementioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Section: Liddle's Syndromementioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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“…This suggested the possibility that other mutations in subunits of the epithelial sodium channel leading to less drastic disruption of channel activity could provide a genetic basis for high blood pressure in subgroups of black people. Working on this hypothesis Baker et al 81 found that a mutation within the sodium channel ␤-subunit, the T594M mutation, was significantly more common in hypertensive black subjects (8.3%) than in normotensive black controls (2.1%); moreover, the presence of this mutation was associated with lower PRA. While the frequency of this variant is relatively low, other studies have also provided evidence for distinct molecular variants in this gene which appear to influence renal sodium excretion in blacks.…”

Section: Renal Epithelial Sodium Channelmentioning

confidence: 99%

Why is plasma renin activity lower in populations of African origin?

Sagnella

2000

J Hum Hypertens

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Plasma renin activity is significantly lower in black people compared with whites independent of age and blood pressure status. The lower PRA appears to be due to a reduction in the rate of secretion of renin but the exact mechanistic events underlying such differences in renin release between blacks and whites are still not fully understood. Nevertheless, given the paramount importance of the renin-angiotensin system in the control of sodium balance, a most likely explanation is that the lower renin is a consequence of differences in renal sodium handling between blacks and whites. The lower PRA does not reflect differences in dietary sodium intake but the evidence available suggests that the low PRA could be part of the corrective mechanisms designed to maintain sodium balance in the presence of an increased tendency for sodium retention in black people. While it is possible that several factors may contribute to the reduced PRA, more recent investigation at

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“…Our patient is a South African black child who tested heterozygous for the βT594M mutation. The association of βT594M mutation and hypertension has been described mainly in studies of black adults from Ghana [8], South Africa [9], USA [10], and London [5]. On the contrary, Hollier et al did not find any association of hypertension and βT594M mutation in their study among black people in Texas and Jamaica [11].…”

Section: Discussionmentioning

confidence: 92%

“…Mutations described that increase the activity of ENaC include C618F and A663T in the C-terminal tail of oc subunit, and T594M mutation in the C-terminal tail of the |3 subunit [4,5]. Schild in 1996 identified a proline-rich motif (PPPxY sequence), also called the PY motif, in the ENaC subunits as a target sequence for mutations causing channel activation in Liddle syndrome.…”

Section: Discussionmentioning

confidence: 99%

A rare cause of systemic hypertension in an African child: Answers

Sigwadi

Biljon

2013

Pediatr Nephrol

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Keywords Hypertensive encephalopathy . Blindness . Hypokalemic metabolic alkalosis . Renin . Aldosterone . βT594M mutation . Amiloride-sensitive epithelial sodium channel (ENaC) . Liddle syndrome Answers 1. The child presented with a hypertensive emergency and had accompanying hypokalemic metabolic alkalosis. Further investigation revealed low renin activity, low serum aldosterone level, and a normal steroid profile, which is suggestive of Liddle syndrome.Other conditions that present with hypertension, hypokalemia, and suppressed renin activity include the syndrome of apparent mineralocorticoid excess, hyperaldosteronism, glucocorticoid-remediable aldo-steronism (GRA), and congenital adrenal hyperpla-sia, which were all excluded for this patient. 2. Liddle syndrome is caused by hyperactivity of the amiloride-sensitive epithelial sodium channel (ENaC), which is highly selective for sodium. Increased Na + reabsorption in the distal convoluted tubules and

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Association of hypertension with T594M mutation in β subunit of epithelial sodium channels in black people resident in London

Cited by 236 publications

References 17 publications

Genetics of arterial hypertension and hypotension

Genetics of arterial hypertension and hypotension

Why is plasma renin activity lower in populations of African origin?

A rare cause of systemic hypertension in an African child: Answers

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