PKDl AND ESSENTIAL HYPERTENSION: A MOLECULAR GENETIC APPROACH 
Stephen T. Reeders, M.D., Assistant Investigator 
The molecular genetics of inherited renal disease 
and hypertension are the focus of Dr. Reeders' 
laboratory. A major element of this work is the de- 
velopment of methods to clone genes (from a 
knowledge of the segregation patterns of mutant 
phenotypes) when the biochemical and cellular 
functions are unknown. 
I. Autosomal Dominant Polycystic Kidney Disease 
(ADPKD). 
ADPKD is one of the most common autosomal 
dominant diseases of humans, affecting 1 in 1,000. 
Progressive cystic dilation arises from all levels of 
the nephron and progresses throughout life. Grad- 
ual impairment of renal function leads to the need 
for dialysis and transplantation, usually in the fifth 
or sixth decades. The underlying biochemical ab- 
normality is not known, although there is increas- 
ing evidence that the primary pathology is tubular 
epithelial hyperplasia. 
Previous work in this laboratory has demon- 
strated that mutations in at least two genes cause 
ADPKD. Most of these mutations disrupt the PKDl 
gene, which was previously mapped by Dr. Reeders 
to the pl3 band of chromosome 16. A series of 
chromosome l6-only interspecies hybrids has been 
created to facilitate the rapid mapping of new DNA 
clones to the I6pl3 region. As a result, several new 
clones have been mapped within an interval of 2-4 
megabases (Mb) surrounding the PKDl gene. Ge- 
netic analysis has identified flanking markers that 
are <3 centimorgans apart. Pulsed-field gel analysis 
has led to the construction of a 2 Mb long-range re- 
striction map of the region between and beyond 
the flanking markers and has allowed the PKDl 
gene to be localized to a region of —650 kb. To ex- 
pedite the recovery of coding sequences from this 
region, an attempt has been made to map and 
clone CG-rich islands that are frequently associated 
with the 5' ends of coding sequences, especially 
those of housekeeping genes. Ten CG-rich islands 
have been mapped within the 650 kb, and five of 
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these have been cloned. Three probes encompass- 
ing CG-rich islands have been used to obtain 
cDNAs from adult kidney libraries. So far, no muta- 
tion of these coding regions has been identified in 
patients. 
II. Essential Hypertension. 
Essential hypertension affects 50 million Ameri- 
cans and contributes to 1 million deaths annually. A 
major element of the susceptibility to hypertension 
is inherited. Risk of hypertension is not, however, 
inherited as a simple MendeUan characteristic but 
as a complex polygenic trait. Thus hypertension 
provides a critical test of the power of genetic link- 
age and molecular genetic methods for detection of 
multiple "risk alleles." 
Dr. Reeders is employing several techniques in 
an attempt to unravel this complex trait. A major 
approach is to study the genetic control of red 
blood cell sodium-lithium countertransport (RBCT), 
a function that is probably performed by one or 
more sodium-hydrogen antiporters. RBCT correlates 
broadly with blood pressure and is probably the 
best available marker for essential hypertension. In 
collaboration with Dr. Chris Dudley (University of 
Oxford), Dr. Reeders has studied the segregation of 
polymorphic loci from chromosome lp35-36 flank- 
ing an Na-H antiporter (APNH) in six families in 
whom multiple individuals were found to be hyper- 
tensive. RBCT levels were measured. The APNH 
locus did not appear to segregate with hyperten- 
sion or RBCT, indicating that this locus does not 
contribute to either blood pressure variability or 
RBCT levels in a major way in these families. 
A genomic cosmid clone containing most of the 
APNH gene was obtained to permit the detection of 
increased polymorphism at this locus and to allow 
study of the organization of the APNH gene. 
Dr. Reeders is also Assistant Professor of Internal 
Medicine and of Human Genetics at Yale University 
School of Medicine. 
Articles 
Hague, WM., Adams, J., Reeders, S.T, Peto, T.E.A., and Jacobs, H.S. 1988. Familial polycystic ovaries: a genetic 
disease? Clin Endocrinol 29:539-605. 
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