CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 5, September/October 2011
AFRICA
243
essential hypertension is controversial.
11-23
Our study examined the prevalence of hypertension and levels
of blood pressure in families of R563Q heterozygous index cases
and supports the theory that in the Xhosa and mixed-ancestry
people in Cape Town, the R563Q mutation is an inherited cause
of hypertension. A single copy of the variant allele of the R563Q
mutation was significantly associated with hypertension: 71
(80%) of the R563Q heterozygous subjects had hypertension,
while 17 (36%) of the R563Q homozygous RR subjects were
hypertensive. Despite the small numbers of participants, families
and individuals studied within the families, the association with
hypertension was significant.
Further support for the causal nature of the R563Q mutation
was demonstrated in the clinically significant differences in
systolic, diastolic and mean arterial BP (Table 1). The differences
in the medians for the heterozygous and homozygous RR groups
were 18 mmHg, 8 mmHg and 12 mmHg for systolic BP, diastolic
BP and MAP, respectively. Additionally, 74% of heterozygous
patients were on antihypertensive treatment versus 30% for the
homozygous RR group, which would tend to reduce the differ-
ences between the groups.
The R563Q mutation appears to be present in our population
at a higher frequency than any of the other single nucleotide
polymorphisms described to date which are causally linked to
hypertension.
4
In our specialist hypertension clinic, the preva-
lence of the mutation was 6.4% for black hypertensives and
4.6% for those of mixed ancestry, and currently all new patients
are routinely tested for the mutation. The homozygous QQ geno-
type was not found in this study. This could be due to the small
number of individuals studied, the small family sizes and the
small number of families. The selection criteria for this study are
also likely to have contributed to the lack of QQ homozygotes:
heterozygotes known to the hypertension clinic were asked to be
involved in the study.
The R563Q mutation is capable of causing the full Liddle’s
phenotype, as was demonstrated in two patients who developed
hypertension and severe persistent hypokalaemia during preg-
nancy. Only one relative was available for study in these kindreds
and she was R563Q homozygous RR and normotensive. The
presence of hypokalaemia in only a minority of the R563Q
heterozygous subjects is consistent with the low penetrance of
hypokalaemia reported in kindreds with other Liddle’s syndrome
mutations,
24,25
and suggests that other genetic or environmen-
tal factors are critical in determining the extent to which the
full Liddle’s syndrome phenotype is expressed. Previously we
reported this mutation in association with hypertension when it
was found by sequencing the genes of the
β
- and
γ
-subunits of
the ENaC in individuals with low renin hypertension.
4
No other
mutations were found when sequencing these subunits so it was
deemed unnecessary to sequence these hypertensive patients.
There are no physiological data on the activity of the ENaC
with this mutation. In Liddle’s syndrome, the R566X truncates
the carboxy terminal of the
b
-EnaC, resulting in impaired inter-
nalisation of the channel and causing a persistently active sodium
channel to reabsorb sodium. The R563Q mutation is three amino
acids from the original Liddle’s mutation and may alter the
protein from the positively charged arginine to the negatively
charged glutamine and potentially alter the three-dimensional
structure of the protein. Therefore, it is possible that this muta-
tion decreases efficient intracellular interactions and internalisa-
tion of the EnaC, thereby increasing active channels on the apical
membrane of the renal tubule. However, further physiological
analyses are required to determine the differences in sodium
channel activity due to the point mutation R563Q.
The R563Q mutation has not been detected in previous
studies which included subjects of African descent.
26,27
Further
research into the geographical distribution of this mutation is
required, particularly within the multi-ethnic black population of
South Africa and Africa. The findings in our study are clinically
relevant as it is anticipated that R563Q heterozygous individu-
als may respond to amiloride, a specific inhibitor of the EnaC.
28
Conclusion
We report the association of the R563Q
β
-ENaC mutation with
hypertension within several kindreds. These findings strengthen
the case for a causative role for R563Q in hypertension, because
the genetic background is more uniform within kindreds than in
the general population.
We thank Donette Baines for assistance with data collection. Funding was
provided by an academic research scholarship from Wyeth Pharmaceuticals
and a research grant from the University of Cape Town.
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