Biology Reference
In-Depth Information
promoter of these genes, a region of DNA found upstream of the coding
sequences. These transcription factors, in some cases, are required for
proper bone development. In other cases, the transcription factors are
required for sensory-cell differentiation at later stages of development. Sur-
prisingly, a wide variety of different transcription factor types have been
found to encode deafness genes. Thus far, the downstream genes activated
by these transcription factors have not been identified, but clearly these
genes are critical for ear development. In this section, a review of some of
the transcription factors known to be required for hearing, and the pheno-
types associated with these transcription mutations, is presented.
In humans, a mutation in the
POU4F3
transcription factor gene (also
called
Brn3c
and
Brn-3.1
) is the basis for progressive, nonsyndromic domi-
nant hearing loss (
DFNA15
) (Vahava et al. 1998). This transcription factor,
which is specifically expressed in the cochlea, has a conserved DNA binding
domain, termed a homeodomain, found in a wide variety of transcription
factors that have been shown to be important for embryonic development
in all species (Semenza 1998). The mutation in
POU4F3
is an 8-bp deletion
within the homeodomain. This deletion results in a frameshift that produces
a protein that is truncated 40 amino acids prematurely. This truncated
POU4F3 protein acts in a dominant fashion to disrupt gene transcription
in the cochlea.
Targeted deletion of the mouse
Pou4f3
gene also leads to profound deaf-
ness, confirming the general importance of this transcription factor in mam-
malian inner ear development (Erkman et al. 1996). In the
Pou4f3
mutant
mice, the sensory cells of the inner ear, as well as their associated nerves,
are not present, although the shape and development of the inner ear is
normal. It is the loss of these cell types that results in deafness, and Pou4f3
protein is clearly required for terminal differentiation of these cell types.
Mutations in a related transcription factor,
POU3F4
, are responsible
for X-linked mixed hearing loss, characterized by stapes fixation and
progressive sensorineural deafness (
DFN3
) (de Kok et al. 1995). This
homeodomain transcription factor has been implicated in bone develop-
ment, since patients with
POU3F4
mutations have a fixed footplate of
the stapes and deficient or absent bone between the lateral end of the
meatus and the basal turn of the cochlea. Patients also exhibit cochlear
defects, suggesting that POU3F4 is involved in multiple stages of ear
development.
POU-type transcription factors are not the only inner ear specific tran-
scriptional regulators. In the mouse, a transcriptional regulator of the fork-
head family,
Foxi1
has been found to encode a nonsyndromic deafness gene
(Hulander et al. 1998).
Foxi1
mutant mice have profound defects in the
structure of the bones of the inner ear, and, as a result, the sensory regions
of the cochlea and vestibular apparatus do not develop. The result is a
“common cavity,” a malformation seen in a portion of human congenital
