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while outer hair cells remain intact into adulthood (Deol and Gluecksohn-
Waelsch 1979; Whitlon et al. 1996). This gene has not yet been identified,
although positional cloning is underway (Bussoli et al. 1997). It is the first
example of a gene essential for the continued survival of one hair cell type,
but not another; it is of particular interest because inner hair cells receive
most of the afferent innervation of the cochlea.
Lastly, supporting cells can also be involved directly in the pathology of
deafness. For example, the
Fgfr3
knockout mutant has a primary effect
upon pillar cell development, which results in impaired hearing (Colvin et
al. 1996). This mutant and others in which specialized cell types around the
cochlear duct are affected emphasize the importance of the correct func-
tion of the whole system, and demonstrate that hair cells alone are not
sufficient to ensure normal auditory function.
Several of the genes involved in mouse neuroepithelial defects are also
involved in human deafness. Usher syndrome type 1B, atypical Usher syn-
drome, and two forms of recessive (DFNB2) and dominant (DFNA11) non-
syndromic deafness are all due to mutations in the
MYO7A
gene (Weil et
al. 1995, 1997; Liu et al. 1997a,b), and so are likely to show similar hair cell
defects as in the shaker1 mutants. The limited observations of temporal
bone pathology in Usher syndrome patients is consistent with a neuroep-
ithelial defect, but no scanning electron microscopy of very early stages of
hair bundle development has been carried out in people with
MYO7A
mutations, nor is it ever likely to be. Both mice and humans with
Myo7a/MYO7A
mutations show hearing impairment and also balance
defects. However, humans with Usher syndrome have the additional feature
of retinitis pigmentosa, but so far only minor differences in retinal function
have been demonstrated in shaker1 mice, with no overt retinal degenera-
tion (Liu et al. 1998, 1999; Hasson et al. 1997). The reason for this differ-
ence is not clear, but may be related to the shorter lifespan of mice
compared with humans, or may be due to differences in the genetic back-
ground, since some humans with
MYO7A
mutations also escape retinal
degeneration.
A form of recessive nonsyndromic deafness (DFNB3) found in an iso-
lated population in Bali is associated with mutation of the
MYO15
gene
(Wang et al. 1998), but there is no histopathology to assess whether the
affected people have short stereocilia, like the shaker2 mouse mutants.
There is an indication that they have a balance problem, similar to the
mouse homologue.
The
POU4F3
gene underlies a dominant form of late-onset, progressive
hearing loss in humans with DFNA15 (Vahava et al. 1998). In mice het-
erozygous for the knockout allele of
Pou4f3
, there is no obvious progres-
sive hearing loss, but again absolute age or genetic background effects might
explain this difference, or possibly the human mutation has a dominant
negative effect. Mice that are homozygous for the knockout mutation show
very little development of sensory hair cells, and the observation of late-
