MOLECULAR BASIS OF DISEASE 
CoRNEUS Van Dor M.D., Ph.D., Assistant Investigator 
Dr. Van Dop's laboratory is concerned with mo- 
lecular processes that alter cellular responsiveness 
to hormones. Particular emphasis is given to gua- 
nine nucleotide-binding coupling proteins and 
their alterations in disease. A second area of study 
relates to molecular lesions of adrenal steroid 
21 -hydroxylase that produce congenital adrenal 
hyperplasia. 
I. Guanine Nucleotide-binding Proteins (G Proteins). 
A variety of extracellular signals alter metabolism 
of mammalian cells by interacting with specific ex- 
tracellular receptor proteins that then activate 
a guanine nucleotide-binding coupling protein 
(G protein). The activated G protein then modu- 
lates an intracellular second messenger system or 
an ion channel. The G proteins, a family of homolo- 
gous proteins, share a heterotrimeric structure in 
which the a-subunit confers functional specificity 
and their common p-y-subunit ties together func- 
tions of different G proteins. Dr. Van Dop's labora- 
tory has been studying several human diseases that 
result in part from altered G protein function. 
These diseases include pseudohypoparathyroidism 
type la and heart failure. 
A. Molecular lesions of G proteins in patients with 
pseudohypoparathyroidism type la. Patients with 
pseudohypoparathyroidism type la and Albright's 
hereditary osteodystrophy commonly have a ge- 
netic deficiency of the a-subunit of the G protein 
that stimulates adenylate cyclase (oiG^). In most af- 
fected families, aG^ deficiency and Albright's heredi- 
tary osteodystrophy are transmitted together in a 
dominant inheritance pattern, although several 
families with autosomal recessive inheritance, and 
therefore probably a different causative genetic de- 
fect, have been described. Studies continue to de- 
termine the molecular defects in the genes encod- 
ing the aG^ that are causative for this disease. 
B. Retinal transducin. The cDNA encoding the 
a-subunit of human retinal transducin has been 
cloned. This rod transducin cDNA shares 88% 
nucleotide sequence homology with the pre- 
viously cloned bovine rod transducin. The ami- 
no acid sequence is also highly homologous be- 
tween these two species, with identical sequences 
around the ADP ribosylation sites for the bacteri- 
al toxins from Bordetella pertussis and Vibrio 
cholerae. 
C. G protein alterations in heart failure. Idio- 
pathic heart failure, a pathophysiologic abnormality 
of heart muscle, diminishes the pumping function 
of the heart, resulting in inadequate delivery of 
blood to tissues and/or circulatory congestion. In 
heart failure the heart muscle manifests reduced re- 
sponsiveness to the chronotropic and inotropic ef- 
fects of sympathetic nervous system stimulation. 
Because cAMP modulates cardiac contractility and 
P-adrenergic receptors are the primary regulators of 
adenylyl cyclase in the heart, components of hor- 
mone-regulated adenylyl cyclase in human hearts 
with idiopathic heart failure were investigated. In 
collaborative studies with Dr. Arthur Feldman (The 
Johns Hopkins University), Dr. Van Dop and his col- 
leagues examined the molecular basis for dimin- 
ished cardiac responsiveness to ^-adrenergic ago- 
nists in hearts from patients with idiopathic heart 
failure who had undergone cardiac transplantation 
and in hearts from Syrian hamsters that develop a 
heritable dilated cardiomyopathy. 
Increased activity of the inhibitory guanine nucle- 
otide-binding regulatory protein (G.) in hearts from 
patients with idiopathic dilated cardiomyopathy 
had previously been demonstrated. Steady-state lev- 
els of the mRNA encoding the a-subunits of several 
G proteins were quantified, using Northern and 
dot-blot analysis. Steady-state levels of mRNAs en- 
coding a-subunits of both G.-3 and G^ were signifi- 
cantly increased in the failing hearts compared with 
nonfailing, control hearts. Among the three differ- 
ent aG. subtypes, mRNA encoding aG.-3 was most 
abundant, that encoding aG.-2 was barely detect- 
able, and that encoding aG.-l was not detectable. 
Coupled with the previous functional studies of 
G proteins in these same failing hearts, these re- 
sults suggest that G protein function in the heart is 
modulated at several levels. 
The cardiomyopathic Syrian hamster has been 
widely studied as a model for congestive heart fail- 
ure in humans. These hamsters inherit as an auto- 
somal recessive trait the propensity to develop con- 
gestive heart failure. Regulation of cardiac adenylyl 
cyclase in these animals was investigated before 
and after they developed heart failure. Pharmaco- 
logic stimulation of adenylyl cyclase in cardiac 
membranes by site-specific agents demonstrated 
Continued 
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