CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 5, September/October 2011
AFRICA
241
The R563Q mutation of the epithelial sodium channel
beta-subunit is associated with hypertension
ESW JONES, EP OWEN, JS DAVIDSON, L VAN DER MERWE, BL RAYNER
Summary
Background:
A high prevalence of the R563Q mutation of
the epithelial sodium channel
β
-subunit has been reported
in South African hypertensives compared with unrelated
normotensive controls. To delineate the effects of this muta-
tion against a more uniform genetic background, this study
investigated the association of the mutation with hyperten-
sion within affected kindreds.
Methods:
Forty-five index patients and members of their
kindreds were studied. Blood pressure, serum potassium and
the presence of the R563Q mutation were determined.
Results:
Of the 136 individuals studied, 89 were heterozygous
for the R563Q mutation and 47 homozygous RR. The mean
arterial pressure was significantly higher in the R563Q
heterozygous group (
p
=
0.005) after adjusting for gender,
race, age and kindred membership. Of the R563Q heterozy-
gous subjects, 71 (80%) had hypertension, while 17 (36%)
of the R563Q homozygous RR subjects were hypertensive.
Six R563Q heterozygous subjects had hypokalaemia and one
R563Q homozygous RR subject had hypokalaemia, but the
difference was not statistically significant. Two heterozygous
patients had Liddle’s syndrome, both occurring during preg-
nancy.
Conclusion:
The R563Q mutation of
β
-ENaC is associated
with hypertension within affected kindreds, but does not
usually cause the full Liddle’s syndrome phenotype.
Keywords:
hypertension, epithelial sodium channel, Liddle’s
syndrome, R563Q mutation
Submitted 24/11/09, accepted 7/9/10
Published online 9/9/10
Cardiovasc J Afr
2011;
22
: 241–244
DOI: 10.5830/CVJA-2010-084
Increased activity of the epithelial sodium channel (ENaC) is
the final common abnormality in several forms of hyperten-
sion: primary aldosteronism, glucocorticoid remediable aldos-
teronism, Liddle’s syndrome and 11-
β
-hydroxysteroid dehydro-
genase-2 deficiency.
1
Activating mutations of either the
β
- or
γ
-ENaC subunits can result in Liddle’s syndrome,
2,3
in which
constitutive reabsorption of sodium leads to hypertension and
hypokalaemia in the presence of low plasma levels of renin and
aldosterone.
We have previously reported the association of the R563Q
mutation of
β
-ENaC with hypertension in black and mixed-
ancestry South African patients, compared with unrelated
normotensives.
4
The purpose of the present study was to inves-
tigate the relationship within affected kindreds, who provided
a more uniform genetic and environmental background against
which the phenotypic effects of the mutation could be assessed.
The R563Q mutation is found in the intracytoplasmic termi-
nal of the
β
-EnaC.
4
This single nucleotide polymorphism substi-
tutes glutamine for arginine at the 563rd amino acid. The variant
allele under investigation in this study was glutamine and it is
thought that the presence of glutamine in this position predispos-
es subjects to hypertension. The R563Q mutation was initially
discovered by sequencing the carboxy terminal of the gene, and
no other variant was found with the mutation in this region.
Methods
The study was approved by the Research Ethics Committee
of the University of Cape Town and all subjects gave signed
informed consent. Index cases attending the hypertension clinic
at Groote Schuur Hospital, and a normotensive subject with
the mutation from the previous study
4
and their kindreds were
approached to participate in the study.
Blood pressure (BP) was measured in the sitting position,
with a mercury sphygmomanometer, after five minutes’ rest. The
mean of two stable readings was used. Hypertension was defined
as systolic BP
≥
140 mmHg and/or diastolic BP
≥
90 mmHg, or
the use of antihypertensive medication. The mean arterial pres-
sure (MAP) was calculated for each patient as one-third of the
pulse pressure plus diastolic pressure. Blood was then drawn for
potassium (K
+
) and DNA analysis. Antihypertensive medication
was not withdrawn prior to BP measurement or blood sampling.
DNA was extracted from whole blood. The carboxy terminal
of the
β
-ENaC was amplified by PCR and the presence of the
R563Q mutation was determined by Sfc-1 restriction enzyme
digestion, and then confirmed by sequencing, as previously
described.
4
The distributions of some of the numerical variables were
skewed, mainly due to extremes in the R563Q heterozygous
group, so they were summarised as medians with interquartile
ranges. Quantile normalisation
5
was used to transform all to a
normal distribution before analysis.
QTDT
6,7
(
index.html) was used to test for association between transformed
numerical variables and R563Q mutation status. QTDT enabled
us to take
degree
of relatedness into account in our analysis and
Division of Hypertension, Groote Schuur Hospital and
University of Cape Town, South Africa
ERIKA SW JONES, MB BCh, PhD
BRIAN L RAYNER, MB ChB, FCP, MMed,
Division of Chemical Pathology, Groote Schuur Hospital
and University of Cape Town, South Africa
E PATRICIA OWEN, PhD
JAMES S DAVIDSON, MB ChB, PhD, FRC Path
LabPlus, Auckland Hospital, Auckland, New Zealand
JAMES S DAVIDSON, MB ChB, PhD, FRC Path
Biostatistics Unit, MRC, Cape Town, South Africa
LIZE VAN DER MERWE, PhD
