The Molecular Basis of Hereditary Diseases 
of the Kidney 
Stephen T. Reeders, M.D. — Assistant Investigator 
Dr. Reeders is also Associate Professor of Internal Medicine and Genetics at Yale University School of 
Medicine. He attended Cambridge University with the intention of majoring in physics, but, realizing that 
developments in molecular biology were providing the basis for studying human disease, he switched to 
medicine and continued to study at Oxford University. After qualifying in medicine, he sought clinical 
training in intensive care, cardiology, nephrology, and neurology. Then, with Sir David Weatherall at 
Oxford, he began to use molecular genetic techniques to study human disease, with emphasis on heredi- 
tary diseases of the kidney, diseases that heretofore had received little attention from geneticists. 
CRITICAL for normal functioning of the kid- 
ney is the integrity of the glomerular base- 
ment membrane (GBM), a complex extracellular 
structure that forms one of the main barriers be- 
tween the blood and the urine. The GBM is com- 
posed of several proteins, including five related 
but subtly different collagens that interact to 
form a chicken-wire mesh holding the membrane 
together. One of the interests of our laboratory is 
Goodpasture syndrome, an autoimmune disorder 
in which, for unknown reasons, autoantibodies 
are suddenly targeted at the collagen components 
of basement membrane in the lungs and kidneys. 
In the kidney, these antibodies produce a sudden 
and devastating inflammation, which frequently 
leads to acute renal failure, irreversible unless 
treated. The nephritis is often accompanied by 
autoimmune lung damage, manifested by bleed- 
ing into the alveoli. 
Previous studies have shown that the probable 
target of Goodpasture autoantibodies is the a 3 
chain of basement membrane collagen. To under- 
stand the pathogenesis more clearly, we under- 
took to isolate and purify the collagen chain so as 
to study its structure. Because the collagen is pres- 
ent in very small amounts and is accompanied by 
four similar proteins, purifying it has proved dif- 
ficult. We have therefore isolated, cloned, and 
sequenced the gene for the a3 chain of basement 
membrane collagen and have used the sequence 
information to predict the primary structure and 
compare this protein with other basement mem- 
brane collagens. 
In collaboration with Billy Hudson (Kansas 
City) , we used knowledge of the primary struc- 
ture to identify several potential antibody-bind- 
ing sites (epitopes) in the q;3 molecule. We syn- 
thesized short peptides and used them to test the 
binding of some of these sites, which we local- 
ized to within a small region of 1 2 amino acids. At 
least one of the peptides has very high affinity for 
Goodpasture antibodies and adsorbs them from 
patients' serum. Knowledge of the epitope struc- 
ture should enable us to develop a means of selec- 
tively adsorbing Goodpasture antibodies, open- 
ing possibilities for a new treatment modality. In 
addition, this information may provide clues to 
the development of autoimmunity in this 
disorder. 
One of the major projects in our laboratory is a 
study of the molecular and cellular pathology of 
autosomal dominant polycystic kidney disease 
(ADPKD), one of the commonest causes of kid- 
ney failure in humans, affecting at least 1 in 
1,000 of the population. The disease is an enor- 
mous burden to families and the community, 
since the majority of patients develop irreversible 
kidney failure in middle life and require dialysis 
or transplantation for survival. 
Having previously ascertained that the majority 
of the inherited mutations in ADPKD lie close to 
the tip of the short arm of chromosome 16, we 
have isolated and cloned a small segment of DNA 
(550,000 base pairs) that includes the mutated 
gene. This region turns out to be extremely gene 
rich, and we have already isolated 22 genes from 
within it. Since we have not been able to detect 
any large-scale deletions or rearrangements af- 
fecting any of the 22, we have begun to examine 
the sequence of these genes in detail and to look 
for mutations that may affect only one or two 
nucleotides. 
Jaap IJdo, a Howard Hughes associate in our 
laboratory, has been interested in the structure of 
telomeres, the ends of chromosomes. He has 
shown that banks of repetitive sequence reminis- 
cent of human telomeres (TTAGGG) are also pres- 
ent at other sites within the human genome. One 
of the most interesting of these banks is embed- 
ded in the middle of the long arm of chromo- 
some 2. Comparison of the chromosome banding 
pattern of humans with that of several closely related 
apes suggests that this region of the chromosome 
contains a point at which two ancestral ape chromo- 
somes fused. Dr. IJdo has cloned this point and 
shown that it consists of a head-to-head telomere- 
telomere fusion. He is investigating the possibility 
that this point of fusion is also responsible for a rare 
form of chromosome fragility that has been observed 
to occur at or very near this site. 
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