Mice as Models for Human Hereditary Deafness - Genetics of Auditory Disorders - page 269

thought likely to have similar inner ear defects (see Table 8.4). In some of
these mutants, the lack of EP and resulting hearing impairment can be vari-
able: some ears show no EP and no melanocytes present in the stria, while
in other ears some melanocytes are detected in the stria, and this invariably
correlates with a measurable EP (although it may be smaller than normal).
This correlation suggests that the melanocytes are indeed vital for EP gen-
eration, and it is not a separate effect of the mutation that leads to the deaf-
ness. Exactly what the melanocytes do remains to be determined, but it is
unrelated to their ability to synthesize melanin pigment because albino
animals have a normal EP and normal, but amelanotic, melanocytes in their
strias.
The mutations associated with a lack of melanocytes in the stria also
lead to white spotting of the coat, which is not surprising because the
melanocytes that populate the skin and hair follicles also migrate from the
neural crest during early development. The genes involved encode tran-
scription factors or growth factors and their receptors, all of which are
necessary at various stages of melanocyte migration, proliferation, differ-
entiation, or survival. For example, the Kit receptor molecule and its ligand
Mgf are required for melanocyte survival. In mice with mutations in either
gene, the melanocyte precursors migrate from the neural crest and can be
detected in the mesenchyme surrounding the otic vesicle, but instead of pro-
liferating and moving into the stria, as in normal mice, they appear to die
(Cable et al. 1995; Steel et al. 1992).
The association between white spotting of the coat and deafness is seen
in many mammals, including humans, and in all cases the deafness can be
variable in its penetrance, and can be unilateral. There are several forms of
pigmentation anomaly associated with deafness in humans, such as piebald
trait due to mutation in the human KIT gene, and Waardenburg syndrome,
which can result from mutations in PAX3 , MITF , EDN3 or EDNRB
(Griffith and Friedman, Chapter 6). It is highly likely that the cochlear
defect in these human syndromes is attributable to a lack of melanocytes
and a reduced or absent EP, but it is most unlikely that it will ever be pos-
sible to test this by measuring the EP in a human.
2.5 Tectorial, Cupular and Otolithic Membrane Defects
A number of mouse mutants have been described with otolithic membrane
or cupular membrane defects (see Table 8.5). These mutants are readily
detected because of the resulting balance anomalies, leading to the classic
shaker-waltzer behaviour of head-tossing, circling and hyperactivity, or
alternatively just tilting of the head. These membranes are formed of extra-
cellular matrix material and lie over the sensory hair cells, providing a
shearing force to facilitate deflection of hair cell stereocilia. Cupular mem-
branes lie over the hair cells of the cristae, and are deflected when the head
moves, causing endolymph to circulate around the semicircular canals,