Genetic Studies in Cardiovascular Disease 
tein determinants involved in these interactions 
are poorly characterized, but the high density of 
negative charges on heparan sulfate indicates that 
the protein domains should include positively 
charged residues. 
After generating many artificial mutations at 
such positions, we have produced the corre- 
sponding proteins by expression in cultured cells 
and analyzed their affinity for heparin. We have 
identified six basic amino acids that mediate the 
high affinity of the active, dimeric enzyme with 
heparin. They form a domain of unique structure, 
which we are attempting to characterize further. 
Essential hypertension presents a yet greater 
challenge, for little biochemical insight is 
usually available. Glucocorticoid-remediable al- 
dosteronism (GRA) is a rare autosomal dominant 
disorder marked by severe hypertension and 
hyperaldosteronism with high levels of abnor- 
mal adrenal steroids. All these manifestations 
can be corrected by the administration of 
glucocorticoids. 
Aldosterone is a steroid involved in the regula- 
tion of the balance of sodium and potassium ions 
and produced in the zona glomerulosa of the adre- 
nal 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 adre- 
nals, and are regulated by the adenohypophyseal 
hormone adrenocorticotropin (ACTH). Their syn- 
thetic pathways share several enzymes, including 
lljS-hydroxylase. Aldosterone synthesis, how- 
ever, requires a unique enzymatic step catalyzed 
by aldosterone synthase, which is normally ex- 
pressed only in the zona glomerulosa. 
In a subject with GRA, we found that unequal 
crossing over between 1 1 (8-hydroxylase and aldo- 
sterone synthase, in close proximity on chromo- 
some 8, had created a new chimeric gene com- 
prising regulatory sequences of 1 lj8-hydroxylase 
and sequences responsible for the catalytic speci- 
ficity of aldosterone synthase. This observation 
explains the ectopic production of aldosterone in 
the adrenal tissue responsible for synthesis of 
glucocorticoids, and the corresponding hor- 
monal control observed in GRA. Although this 
finding provides a clear interpretation of the 
complex physiology of a rare form of hyperten- 
sion, its significance for our understanding of the 
more common forms of essential hypertension 
remains to be determined. 
Mutations of human lipoprotein lipase that 
impair the enzyme's ability to regulate lipid 
metabolism are shown superimposed upon a 
schematic rendering of the backbone of a ho- 
mologous enzyme, human pancreatic li- 
pase. The three circled residues define the 
triad directly involved in catalysis. 
From Lalouel, f.-M., Wilson, D.E., and Iver- 
ius, P.-H. 1992. Curr Opin Upidol 3:86-95. 
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