generation, known as gyrate atrophy of the choroid 
and retina. The molecular basis and functional con- 
sequences of 15 mutations of this gene have been 
determined. The number and distribution of these 
mutations in a well-defined population group of 
Finns with a high frequency of gyrate atrophy have 
been determined, with the aim of understanding 
factors that influence the origin and spread of such 
mutations. Studies of the gene for phenylalanine 
hydroxylase have delineated a mutant allele that ac- 
counts for a substantial fraction of the mutations 
responsible for PKU in American blacks. Finally, 
with collaborators at The Johns Hopkins University, 
Dr. Valle has detected the first mutation in the G a 
s 
gene, which causes pseudohypoparathyroidism, a 
dominantly inherited disorder in calcium homeo- 
stasis. 
The laboratory of Assistant Investigator Cornelis 
Van Dop, M.D., Ph.D. (formerly Children's Hospi- 
tal, Boston) has investigated the molecular basis of 
altered hormone responsiveness in human disease. 
The two primary diseases being studied are pseu- 
dohypoparathyroidism, which is manifested as re- 
sistance to parathyroid hormone, and idiopathic 
heart failure, a sporadic disease that has significant 
mortality and is the most common reason for heart 
transplantation. The clinical manifestations in both 
these diseases result in part from reduced respon- 
siveness of the affected tissues to hormones and 
neurotransmitters that increase cAMP synthesis in 
the tissue. The studies of this laboratory have dem- 
onstrated reduced functional levels of specific 
membrane proteins that couple signals from hor- 
mone receptors on the outside of the cell across 
the cell membrane to the en2yme adenylyl cyclase 
that synthesizes cAMP inside the cell. The molecu- 
lar mechanisms that affect this normal transmem- 
brane signaling system in these diseases are being 
examined. 
The genetics of two different human disorders 
have been studied by the laboratory of Investigator 
Jonathan G. Seidman, Ph.D. (Harvard Medical 
School). The chromosomal position of the locus re- 
sponsible for familial hypertrophic cardiomyopathy 
(FHC) has been identified. This is an important first 
step toward identifying the gene responsible for 
this disorder and defining the molecular basis of 
cardiac hypertrophy. The role of somatic gene rear- 
rangement of T cell receptor p-chain genes in an 
animal model of diabetes was examined. Studies of 
NOD (non-obese diabetic) mice bearing a rear- 
ranged functional T cell receptor p-chain transgene 
suggest that somatic gene rearrangement of p-chain 
genes is not required to cause this autoimmune dis- 
ease. 
An interest in the identification of genetic deter- 
minants of complex phenotypes in common dis- 
ease has led the research group of Investigator 
Jean-Marc Lalouel, M.D., D.Sc. (University of Utah) 
to investigate the factors responsible for heritable 
disorders of lipid metabolism and early occurrence 
of myocardial infarction. At present work is focused 
on the molecular genetics of lipoprotein lipase, a 
key enzyme in triglyceride metabolism. Cloning and 
sequencing of the entire coding region of the gene 
has revealed two point mutations. The functional 
significance of the first mutation was established 
when lipoprotein lipase inactive, but immunoreac- 
tive, protein was found transiently in vitro in a sys- 
tem for gene expression. A relationship between 
carrier status and hypertriglyceridemia was demon- 
strated after molecular identification of carriers 
among relatives of the proband. Investigations will 
now focus on the possible role of lipoprotein lipase 
defects in familial hypertriglyceridemia and on the 
relationship between the structure and function of 
the enzyme. 
The work of Assistant Investigator Stephen T. 
Reeders, M.D. (Yale University) involves approaches 
toward the elucidation, at the molecular or DNA 
level, of the defects associated with the develop- 
ment of autosomal dominant polycystic kidney dis- 
ease and essential hypertension. The methodology 
employed, often termed the reverse genetic ap- 
proach, allows investigators to work toward the 
isolation and study of the gene(s) responsible for 
these diseases, using as a starting point families in 
which one can demonstrate cosegregation of the 
disease with a previously defined genetic marker. 
Once cosegregation, or linkage, is observed, molec- 
ular biological approaches such as DNA cloning 
and sequence analysis from the region of the chro- 
mosome thought to be implicated are employed. 
Differences in the DNA from within this region be- 
tween normal and affected individuals are then 
sought. 
The laboratory of Investigator David M. Kurnit, 
M.D., Ph.D. (University of Michigan) employs amul- 
tifaceted approach to the study of Down syndrome 
and development. The use of molecular probes on 
chromosome 2 1 enables this group to examine the 
molecular structure of chromosome 21 and study 
the origins of trisomy 21 leading to Down syn- 
drome, a leading cause of heart defects and mental 
retardation in humans. In addition, the study of ex- 
pressed sequences on chromosome 21 enables the 
Continued 
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