Hansson JH, Suzuki H, Schild L, Rossier B, Lifton RP
Genetic heterogeneity of Liddle's syndrome
AHA Council for High Blood Pressure Research
Hypertension
(Sep) 26:537 (abst) 1995
Liddle's syndrome, first described in 1963, is an autosomal dominant form of
human
hypertension characterized by severe hypertension, variable hypokalemia, and
negligible secretion
of aldosterone (hence pseudoaldosteronism). The hypertension responds well
to triamterene, a
specific inhibitor of the collecting duct apical membrane sodium channel.
These findings
suggested that the hypertension might be caused by excessive sodium
reabsorption in the distal
nephron via a mineralocorticoid-regulated, amiloride-sensitive, epithelial
sodium channel which is
indirectly coupled to potassium secretion. This channel is comprised of
three subunits (alpha, beta
and gamma). Last year, this same group demonstrated complete linkage to an
abnormal beta
subunit of the epithelial sodium channel in Liddle's original kindred (Cell
79: 407-414, 1994).
There was a premature stop codon that truncated the cytoplasmic carboxyl
terminus in affected
subunits. Analysis of four other kindreds showed either premature
terminations or frameshift
mutations in this same gene. These findings were the first identification of
the molecular basis of
an inherited from of hypertension, and motivated may researchers to study
candidate genes in the
hypertensive populations. However, some Liddle's kindreds have normal beta
subunits, which motivated them to
study other subunits of this channel. They found a point mutation which
introduced a premature
stop codon, truncating 76 aminoacids. Expression of the mutant protein in
the context of normal
alpha and beta subunits revealed a four fold increase in sodium conductance.
These findings
indicate that Liddle's syndrome is genetically heterogeneous, involving at
least two subunits of the
epithelial sodium channel.
(R. Star)
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AHA Council for High Blood Pressure Research
H: Pathophysiology :
Genetics
H: Special problems :
Endocrine hypertension