model of inheritance, optimal family structures, and 
candidate-gene versus general-linkage approaches. 
Work in this laboratory follows two directions. 
On the one hand, rare Mendelian syndromes are ex- 
amined in the hope that unraveling their molecular 
basis may shed new light on the pathophysiology of 
commoner forms of essential hypertension. On the 
other hand, an attempt is made to identify genetic 
determinants at play in essential hypertension by ap- 
plying linkage analysis in a large series of hyperten- 
sive siblings. Richard Lifton and Xavier Jeunemaitre 
led each project. 
Glucocorticoid-remediable aldosteronism (GRA) 
is a rare autosomal dominant disorder marked by 
severe hypertension and hyperaldosteronism with 
high levels of abnormal adrenal steroids. All these 
manifestations can be corrected by the administra- 
tion of glucocorticoids. 
Aldosterone is a steroid involved in the regulation 
of sodium and potassium ion balance. It is produced 
in the zona glomerulosa of the adrenal gland under 
the primary control of the renin-angiotensin system. 
By contrast, glucocorticoids exert their effects on 
carbohydrate metabolism, are produced by the zona 
fasciculata of the adrenals, and are regulated by the 
adenohypophyseal hormone adrenocorticotropin 
(ACTH). 
The synthetic pathways of aldosterone and the 
glucocorticoids share several enzymes, including 
11/3- hydroxylase. Aldosterone synthesis, however, 
requires a unique enzymatic step catalyzed by aldo- 
sterone synthase, which is normally expressed only 
in the zona glomerulosa. In a subject with GRA, it 
was found that an unequal crossing over between 
1 1/3-hydroxylase and aldosterone synthase, in close 
proximity on chromosome 8, had created a new chi- 
meric gene composed of regulatory sequences of 
1 1/3-hydroxylase and sequences responsible for the 
catalytic specificity of aldosterone synthase. 
This observation explains the ectopic production 
of aldosterone in the adrenal tissue responsible for 
synthesis of glucocorticoids and the corresponding 
hormonal control observed in GRA. It provides a 
clear interpretation of the complex physiology of a 
rare form of human hypertension. 
Another study has been initiated dealing directly 
with the common phenotype of essential hyperten- 
sion. Lacking a well-defined mode of inheritance, 
linkage is being sought in hypertensive siblings, fol- 
lowing a protocol that does not require any assump- 
tion regarding the mode of inheritance. Rather, link- 
age is inferred when the number of alleles shared by 
hypertensive siblings at a marker locus significantly 
exceeds that expected under the hypothesis of inde- 
pendent segregation between disease and markers. 
In collaboration with Dr. Roger Williams, 244 
pairs of hypertensive siblings were studied and DNA 
samples prepared from all study subjects. Of the nu- 
merous metabolic pathways that could be involved 
in the pathogenesis of hypertension, the renin- 
angiotensin system was singled out at the outset in 
light of its central roles in salt and fluid homeostasis 
and the maintenance of vascular tone. 
Stimulation or inhibition of this system respec- 
tively raises or lowers blood pressure. Conse- 
quently, each component of the system represents a 
potential candidate in the etiology of hypertension. 
In response to salt depletion or a drop in blood pres- 
sure, renin (REN), an aspartyl protease secreted by 
the kidney, hydrolyzes angiotensinogen (ANG) to 
release the decapeptide prohormone angiotensin I. 
Further cleavage of angiotensin I by dipeptidyl 
carboxypeptidase, the angiotensin-converting en- 
zyme (ACE), produces angiotensin II, leading to 
vasoconstriction and increased sodium reabsorp- 
tion through stimulation of aldosterone secretion. 
Highly informative polymorphic markers at each of 
these three loci have been used to perform linkage 
tests in hypertensive siblings. The studies with REN 
and ACE have been completed, and the study with 
ANG is under way. 
Animal models have offered suggestive evidence 
for a role of either REN or ACE in the pathogenesis of 
hypertension in selected laboratory strains of rats. 
The possible involvement of ACE in human hyper- 
tension was suggested in two studies recently 
published. Both reported significant linkage be- 
tween blood pressure and an anonymous marker 
of the growth hormone gene in the immediate 
vicinity of the gene encoding ACE in a strain of 
spontaneously hypertensive rats, the stroke-prone 
SHR-SP. 
The potential significance of this finding was un- 
derlined by the success of ACE inhibitors in the 
treatment of essential hypertension in humans. A 
highly informative marker was developed at the hu- 
man growth hormone locus, and tight linkage be- 
tween growth hormone and ACE was confirmed in 
humans. This marker was characterized in hyperten- 
sive siblings. There was no evidence in support of 
genetic linkage in these siblings, whether the entire 
sample or subsets based on earlier onset or greater 
severity were selected. 
Similar results were obtained at the REN locus. 
These negative results indicate that molecular vari- 
ants of these genes do not commonly contribute to 
the pathogenesis of essential hypertension in hu- 
mans. They also represent the beginning of a sus- 
tained investigation of the genetics of essential hy- 
pertension. 
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