Genetic Basis of Hearing Loss 
Geoffrey M. Duyk, M.D., Ph.D. — Assistant Investigator 
Dr. Duyk is also Assistant Professor of Genetics at Harvard Medical School and a member of the Eaton- 
Peabody Laboratory at the Massachusetts Eye and Ear Infirmary. He received his undergraduate degree 
at Wesleyan University and his M.D. degree and a Ph.D. degree in biochemistry at Case Western Reserve 
University. After internship and residency at the University of California, San Francisco, he held a 
fellowship in medical genetics under the direction of Charles Epstein. His postdoctoral research work was 
also at UCSF, with David Cox and Richard Myers. While at UCSF, Dr. Duyk was awarded an HHMI 
Physician Research Fellowship and was a Lucille P. Markey Scholar in Biomedical Science. 
HEARING loss is the commonest form of sen- 
sory impairment. In the United States the in- 
cidence of congenital deafness is approximately 
1 per 1,000, and at least half of these cases are 
likely to be determined genetically. It is esti- 
mated that by age 65 one in six of us will have a 
clinically significant hearing loss. While environ- 
mental factors play a role in hearing impairment, 
genetic factors often determine predisposition. 
Deafness is a major aspect of over 100 defined 
genetic disorders. 
Our laboratory is interested in sensorineural 
hearing loss in which the abnormality should lie 
along the pathway between the sensory receptors 
of the inner ear and the auditory centers of the 
brain. Our strategy is to combine genetic map- 
ping and positional cloning with candidate gene 
approaches to identify genes responsible for 
hearing loss and to further our understanding of 
the molecular mechanisms of hearing. 
Candidate Genes 
Within the inner ear reside the sensory organs 
for hearing and balance. Both of these systems 
represent mechanical transduction. In each, a 
specialized "hair cell" serves as a sensor of sound 
or motion. Hair cells are highly polarized, with 
the basal surface forming synapses with afferent 
and efferent nerve fibers. Finger-like projections 
referred to collectively as the hair cell bundle are 
distinctive features of the hair cell's apical sur- 
face. Deflection of the hair cell bundle by the 
sensory input activates mechanically sensitive 
ion channels, initiating signal transduction. This 
process is distinct from other sensory systems 
such as taste, olfaction, and vision, where a ligand 
binds to a specific receptor, which in turn acti- 
vates a second messenger system to initiate sen- 
sory transduction. The molecular components of 
this highly specialized mechanical sensory sys- 
tem are logical targets for specific mutations re- 
sulting in hearing loss. 
In collaboration with David Corey (HHMI, 
Massachusetts General Hospital), we have begun 
the process of identifying the molecular compo- 
nents of the hearing apparatus by combining mo- 
lecular biological and biophysical approaches. 
Although extensive microanatomical and bio- 
physical characterization of this apparatus has 
been undertaken, little biochemical or molecular 
information is available. As a starting point, we 
are constructing cDNA libraries from microdis- 
sected inner ear material highly enriched for hair 
cells. In addition, we are exploring strategies for 
analyzing mRNA populations of single cells with 
the polymerase chain reaction (PGR) technique 
to augment the traditional approaches for re- 
covering and studying genes from specialized tis- 
sue sources. As we identify components of the 
sensory transduction pathway, human and mu- 
rine homologues will be recovered and mapped 
to specific chromosomes, and closely linked DNA 
polymorphic markers will be identified. The de- 
rived information will be an important resource 
as we begin our search for the mutations responsi- 
ble for this group of inherited disorders. 
"Reverse Genetics" 
The genetic analysis of hearing loss in human 
populations is complicated by the difficulty of 
diff^erentiating many of these syndromes (genetic 
heterogeneity) and the fact that deaf individuals 
often intermarry (nonassortive mating). As a con- 
sequence, most of the families suitable for study 
are small, increasing the problem of placing the 
disease locus with the degree of precision re- 
quired to clone the gene. The availability of 
mapped candidate genes helps to bridge the gap 
between genetic and physical mapping. Analysis 
of these small families will be enhanced by the 
availability of dense genetic maps. Toward that 
end, we have developed an efficient technique 
for the construction of genomic libraries aug- 
mented for selected classes of simple sequence 
repeats (SSRs). SSRs correspond to runs of di-, 
tri-, or tetranucleotide sequences (e.g., [CA]„ or 
[GGC]„) that often demonstrate length polymor- 
phisms detectable by PGR assay. These libraries 
will aid in the production of high-resolution ge- 
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