Mice as Models for Human Hereditary Deafness - Genetics of Auditory Disorders - page 259

A glance at Table 8.2 shows that many of the known genes underlying
inner ear malformations are transcription factors, which is not surprising
given that these defects must arise very early in development. However,
one surprising recent finding has been that genes involved in ionic
homeostasis of the ear can be involved in the pathology. For example, the
shaker-with-syndactylism mutant was originally reported as showing thin
semicircular canals (Deol 1963), but this defect is now known to result from
mutation of the Slc12a2 gene, encoding a cotransporter implicated in ion
transport in marginal cells of the stria vascularis (Dixon et al. 1999). All
endolymphatic compartments collapse to some extent around the time of
birth in this mutant, including the lumen of each semicircular canal, sug-
gesting failure of normal endolymph production (Deol 1963). It seems
likely that the narrower template of a collapsed lumen leads to the forma-
tion of a thinner canal as the cartilage is laid down around it (Dixon et al.
1999).
Several of the mutants in this group have human homologues. Human
genes are symbolized in capitals, and mouse genes are in lower-case letters,
but otherwise they generally have the same symbol. The Eya1 and Pou3f4
mouse mutants show broadly similar malformations, as seen in the human
syndromes branchio-oto-renal syndrome (with mutations in the human
EYA1 gene) and X-linked mixed deafness with gusher (mutations in the
human POU3F4 gene), respectively (Griffith and Friedman, Chapter 6). In
particular, the wide internal auditory meatus observed in X-linked mixed
deafness with gusher, which is believed to allow direct communication of
perilymph with cerebrospinal fluid, is also seen in the mouse mutant. The
third example is the histinaemia mouse mutant, in which a mutation in the
histidase gene leads to an excess of histidine in the mother, which in turn
seems to have a teratogenic effect on the developing fetus, causing mild
inner ear malformations (Kacser et al. 1979). Similar malformations have
not been reported in humans suffering from maternal histidinaemia,
although speech defects have been described. Pax3 mutations in splotch
mutant mice lead to malformations of the inner ear in homozygotes (Deol
1966a), but these mice die before birth with gross neural tube defects. A
single human homozygous for a PAX3 mutation survived and has been
described as deaf with white skin and hair, but it is not known whether the
child had malformed inner ears (Zlotogora et al. 1995). Mutations in several
other genes in this group in humans, including NF1 , COLA1 , and ISK , can
be associated with hearing impairment, but it is not known whether any
inner ear malformation is present in affected people.
2.3 Neuroepithelial Defects
Neuroepithelial defects involve a primary abnormality in the neuroepithe-
lia of the inner ear, such as the organ of Corti in the cochlea, the maculae
of the saccule and utricle, and the cristae of the ampullae at the end of each