Polymorphisms in the carboxy-terminus of the epithelial sodium channel in rat models for hypertension (original) (raw)
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BMC medical genetics, 2005
Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC beta and gamma subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system. Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests. Two commonly occurring betaENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel gammaENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly h...
Hypertension Research, 2004
Liddle's syndrome is an autosomal dominant disease characterized by sodium-sensitive early hypertension and mutations in either the-or-subunit of the amiloride-sensitive epithelial sodium channel encoded by SCNN1B and SCNN1G. We sequenced the 381 bp-coding regions in exon 13 of SCNN1B and the 381 bp-coding regions in exon 12 of SCNN1G in 948 and 953 Japanese patients with hypertension, respectively. In the SCNN1B gene, we identified three missense mutations, P592S (n 3), T594M (n 2), and E632K (n 1) in a heterozygous state in addition to four synonymous ones, Ile515 (n 1), Ser520 (n 19), Ser533 (n 1), and Thr594 (n 11). In the SCNN1G gene, we identified three missense mutations, A578V (n 1), P603S (n 1), and L609F (n 1) in a heterozygous state in addition to two synonymous ones, Ile550 (n 1) and Leu649 (n 91, heterozygous; n 2, homozygous). We did not identify the same mutations previously reported in Liddle's syndrome kindreds. Two of the six hypertensive patients with missense mutation in the SCNN1B gene showed atypical renin and aldosterone levels, though one of them was diagnosed with renovascular hypertension. One patient with T594M in the SCNN1B gene was resistant to hypertension. The roles of these missense mutations in the SCNN1B or SCNN1G gene identified in hypertensive patients are not clear in the pathogenesis of hypertension and the regulation of electrolytes. Thus, further investigation of these mutations, including functional analyses, will be needed. (Hypertens Res 2004; 27: 333-338)
Genetic Analysis of the β Subunit of the Epithelial Na + Channel in Essential Hypertension
Hypertension, 1998
Mutations of the last exon of the  subunit of the amiloride-sensitive epithelial Na ϩ channel (ENaC) can lead to Liddle's syndrome, a rare monogenic form of hypertension. The objective of this study was to test whether more subtle changes of ENaC could be implicated in essential hypertension. After determination of the ENaC coding gene organization (12 exons spanning 23.5 kb), a systematic screening of the last exon of the gene was performed in 525 subjects (475 whites, 50 Afro-Caribbeans), all probands of hypertensive families. This search was extended to the remaining 11 exons in a subset of 101 probands with low-renin hypertension. Seven amino acid changes were detected: G589S, T594M, R597H, R624C, E632G (last exon), G442V, and V434M (exon 8). These genetic variants were more frequent in subjects of African origin (44%) than in whites (1%). The functional properties of the variants were analyzed in Xenopus oocytes by two independent techniques, ie, electrophysiology and 22 Na ϩ uptake. Small but not significant differences were observed between the variants and wild type. The clinical evaluation of the family bearing the G589S variant, which provided the highest relative ENaC activity, did not show a cosegregation between the mutation and hypertension. The present study illustrates the difficulty in establishing a relation of causality between a susceptibility gene and hypertension. Furthermore, it does not favor a substantial role of the ENaC gene in essential hypertension.
American Journal of Hypertension, 2000
We evaluated the association of a common polymorphism in ␥ENaC, consisting in a C to G transversion in codon 649, with essential hypertension and to the pressor response to salt in whites. Two hundred fifteen essential hypertensive patients, and 137 normotensive controls were genotyped for the ␥649 ENaC polymorphism by polymerase chain reaction method and diagnostic restriction enzyme digestion. The genotype distribution of the ␥649 ENaC polymorphism in the hypertensives, 129 CC (60%) and 86 CG/GG (40%) was not significantly different from that of the control group, 84 CC (61%) and 53 CG/GG (39%) (P ؍ ؍ .81). Salt sensitivity was assessed in a group of 48 patients by 24-h mean blood pressure response to changes in salt intake. Nineteen patients were diagnosed as salt sensitive, whereas 29 had salt-resistant hypertension. The ␥649 ENaC genotype distribution in salt-sensitive patients was 12 CC (63%) and 7 CG/GG (37%), not significantly different from the distribution in the salt-resistant group, 19 CC (65%) and 10 CG/GG (35%), P ؍ ؍ .87. The changes in systolic, diastolic, and mean blood pressure as measured by ambulatory blood pressure monitoring, and in plasma renin activity and plasma aldosterone induced by high salt diet were not different among the ␥649 ENaC genotypes. In the present study we found no association between the ␥649 ENaC polymorphism and essential hypertension or salt sensitivity. Although these data do not support a major causative role for this polymorphism, we cannot exclude that a functional mutation elsewhere in ENaC might be associated with essential hypertension.
Polymorphisms of the γ subunit of the epithelial Na+ channel in essential hypertension
Journal of Hypertension, 1999
Objective The ã subunit of the epithelial Na channel (ãENaC) has been implicated in Liddle's syndrome. The objective of this study was to examine its status in essential hypertension. Design and methods The search for molecular variants was performed using the SSCP technique after determination of the intron±exon boundaries of the transcribed sequence. We found an additional 205 bp intron splitting the published exon 10 in two. The last exon of ãENaC was tested with samples from a series of 245 normotensive patients and 453 hypertensive subjects (383 Caucasians, 70 Afro-Caribbeans), all probands of hypertensive families in the HYPERGENE data set. The search was extended to the other 11 transcribed exons in a subset of 65 patients with low-renin pro®le. Results Four neutral polymorphisms were detected, three in the third exon of the gene (T387C, T474C, C549T) and one in the last exon (C1990G). These four variants were found with similar frequencies in hypertensive and normotensive Caucasian subjects as well as in patients with low-renin pro®le. Hypertensive Caucasians and hypertensive subjects of African ancestry also had similar frequencies. Lastly, we found two rare mutations, one the insertion of a proline residue at position 594 of the mature protein (594insP), the other an Arg-to-His substitution at position 631 (R631H). Compared to wild-type (1.00 6 0.42, n = 26), expression of the 594insP (1.10 6 0.43, n = 26) and R631H (0.97 6 0.43, n = 26) variants in Xenopus oocytes produced no signi®cant increase in Na current. Conclusions Screening of the entire coding sequence of ãENaC does not suggest that this subunit is frequently involved in essential hypertension.
Genetic Analysis of the b Subunit of the Epithelial Na1 Channel in Essential Hypertension
2000
Mutations of the last exon of the b subunit of the amiloride-sensitive epithelial Na 1 channel (bENaC) can lead to Liddle's syndrome, a rare monogenic form of hypertension. The objective of this study was to test whether more subtle changes of bENaC could be implicated in essential hypertension. After determination of the bENaC coding gene organization (12 exons spanning 23.5