Biology Reference
In-Depth Information
8
Mice as Models for Human
Hereditary Deafness
KAREN P. S TEEL,ALEXANDRA ERVEN, and AMY E. KIERNAN
1. Introduction
Investigating the biological basis of genetic hearing impairment in humans
is very difficult. Temporal bone specimens can be analysed and have pro-
vided vital clues to aid gene identification in the past (Robertson et al. 1998),
but in most cases these specimens come from elderly people who have end-
stage cochlear pathology. Thus, such tissue may not be helpful in determin-
ing the cause of deafness early in life. A very common, if not universal, result
of cochlear dysfunction is hair cell degeneration, which also leads to dedif-
ferentiation of supporting cells, and this gives few clues to the cause of deaf-
ness. Yet, there is little evidence for the degeneration of hair cells being the
cause of cochlear dysfunction, rather than the result, in genetic deafness.
Some electrophysiology can be carried out in humans, and this may distin-
guish conductive from sensorineural deafness, and cochlear from central
auditory system pathology, but detailed physiological analysis of the func-
tion of the ear, such as endocochlear potential measurements and single hair
cell recordings, cannot be undertaken in humans. Developmental studies are
also not possible in humans, but it is only by studying the earliest stages of
dysfunction that the reasons for deafness can be uncovered.
Animal models do not have these disadvantages because they can be
studied at any stage of development, and functional studies can be carried
out on anaesthetised animals or isolated preparations from the ear.
Also, experimental manipulations, such as transgenic or gene knockout
approaches, are feasible. Furthermore, the early stages of positional cloning
of deafness genes (Mueller, Van Camp, and Lench, Chapter 4) is facilitated
by the ability to generate very large numbers of animals all known to be
carrying the same deafness mutation. This allows much more accurate local-
ization in mapping the mutation than could be achieved in humans with
their small family sizes and heterogeneity. Mice are the obvious choice of
model because of the profusion of deaf mutants already known, the rapid
generation time, and the use of this species as the major mammalian model
in genome analysis.
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