whether the hearing loss in affected family members 
is genetic or acquired. If the hearing loss is proved 
to be hereditary, analysis of pedigrees may be fur- 
ther complicated by genetic heterogeneity and non- 
assortive mating. The broad goal of the laboratory of 
Assistant Investigator Geoffrey M. Duyk, M.D., Ph.D. 
(Harvard Medical School) is to develop the methods 
and resources to identify and study the genetic basis 
for nonsyndromic hearing loss. Toward these ends, 
the research focuses on the construction of a very 
high resolution human genetic linkage map and defi- 
nition of the basis for hearing at the molecular level. 
The mapping of genes of known function to sites 
on human and mouse chromosomes can lead to 
identification of candidate genes for human genetic 
disorders or inherited mouse mutations. The gene 
for peripheral myelin protein (PMP-22) has been 
mapped to mouse chromosome 1 1 and human chro- 
mosome 71p by the laboratory of Investigator Uta 
Francke, M.D. (Stanford University) and was subse- 
quently shown to be mutated in the dominant neuro- 
logic mutation Trembler in the mouse. The gene is 
also likely to contribute to the hereditary motor and 
sensory neuropathy Charcot-Marie-Tooth disease, 
type lA, since it is located on the small duplicated 
DNA segment that is associated with this disease. A 
candidate gene for contributing to the Prader-Willi 
syndrome phenotype was identified by mapping the 
small nuclear ribonucleoprotein polypeptide N 
gene to the submicroscopic deletion region critical 
for this syndrome on chromosome 1 5q. The gene is 
imprinted on the maternally derived chromosome 
in mice. Molecular genetic analysis of a human 
X-autosome translocation identified an associated 
deletion and conserved sequence motifs at all three 
breakpoints. This is the second human constitu- 
tional translocation that has been analyzed at this 
level, and the results suggest possible mechanisms. 
In an induced translocation in transgenic mice, 
clusters of transgenes were localized to chromo- 
somal sites on both translocation chromosomes, 
again suggesting models regarding the origin of this 
translocation event. In the growth hormone insensi- 
tivity syndrome, a rare autosomal recessive disorder, 
additional mutations in the growth hormone recep- 
tor gene were identified in patients from different 
parts of the world. These data throw light on the 
origin and nature of mutations that lead to a severe 
growth deficiency. 
Common cardiovascular disorders such as coro- 
nary artery disease and hypertension constitute 
broad clinical classes representing multiple etiologi- 
cal entities, where many genes and environmental 
determinants are likely to be involved. Work on the 
genetics of hypertension in the laboratory of Investi- 
gator Jean-Marc Lalouel, M.D., D.Sc. (University of 
Utah) follows two directions: molecular investiga- 
tions of rare Mendelian syndromes of hypertension 
and linkage analysis in a large series of hypertensive 
siblings. In glucocorticoid-remediable aldosteron- 
ism, a rare disorder marked by severe hypertension 
and high levels of abnormal steroid hormones, an 
unequal crossing over between genes involved in 
the biosynthesis of adrenal steroids creates a new 
chimeric gene with expression that explains the ob- 
served pathophysiology. Linkage studies of essential 
hypertension are under way and have first concen- 
trated on the renin-angiotensin system. 
Investigator Arthur L. Beaudet, M.D. (Baylor Col- 
lege of Medicine) and his colleagues use recombi- 
nant DNA techniques to study human genetic dis- 
eases. One project concerns the role of proteins that 
mediate adhesion of white blood cells to blood ves- 
sel walls. Mutations are being prepared in mice to 
study the genes encoding these proteins in models 
of various inflammatory diseases and atherosclero- 
sis. Naturally occurring genetic variation in the hu- 
man population is being evaluated to examine the 
role of these genes in common adult disease pro- 
cesses. In other studies, automated methods for DNA 
testing are being developed in order to screen for 
couples at risk for having a child affected with cystic 
fibrosis. A mutant mouse model for cystic fibrosis 
also is under development. Other projects are under 
way to clone the genes for two human conditions 
associated with mental retardation, the Prader-Willi 
and Angelman syndromes. 
Investigator Graeme I. Bell, Ph.D. (University of 
Chicago) and his colleagues are studying the causes 
of non-insulin-dependent, or type 2, diabetes melli- 
tus (NIDDM). Genetics and molecular biology 
are being used to identify and characterize the 
genes that increase the risk of developing this com- 
mon disorder of aging adults. Genetic studies of fam- 
ilies with a highly penetrant, autosomal dominant 
form of NIDDM that may affect children and adoles- 
cents, termed maturity-onset diabetes of the young 
(MODY), have identified diabetes-susceptibility 
genes on chromosomes 7 and 20. The locus on chro- 
mosome 7 encodes the glycolytic enzyme glucokin- 
ase, which plays an important role in regulating and 
integrating glucose metabolism in insulin-secreting 
cells of the pancreas and in the liver. Twenty differ- 
ent mutations in the glucokinase gene associated 
with the development of NIDDM have been identi- 
fied to date in French, British, Swedish, Japanese, 
and African-American patients, indicating that they 
are not restricted to a particular ethnic or racial 
group. The identity of the gene on chromosome 20 
has not been determined, and studies are under way 
GENETICS 137 
