Biology Reference
In-Depth Information
inner ear defects. Thus far, no human patients have been identified with
alterations in
Foxi1
, but it is considered a good candidate for a human deaf-
ness gene.
Gene-targeted mutagenesis of
Math1
, the mouse homologue of the
Drosophila
transcription factor atonal, has been found to cause deafness in
mice (Bermingham et al. 1999). Most significantly, the hair cells in these
mice never form, indicating that this transcription factor regulates the
genesis of hair cells.
Mutations in transcription factors can also result in syndromic deafness.
A summary of these transcription factors and their associated syndrome
genes is shown in Table 2.4. Of these diseases, the best characterized is
Waardenburg syndrome (WS). Waardenburg patients have an auditory-
pigmentary syndrome characteristic of a defect in melanocyte development
(reviewed in Read and Newton 1997). Most patients have mutations in the
transcription factor
PAX3
and, depending on the penetrance of the muta-
tion, patients can exhibit dystopia canthorum (lateral displacement of eyes;
WS type 1) or musculoskeletal abnormalities (WS type 3), in addition to
sensorineural deafness and depigmentation. Patients with deletions of the
PAX3
gene have phenotypes indistinguishable from patients that have
small substitutions in the DNA-binding domains of
PAX3
, and it has been
observed that two very similar mutations can result in different phenotypes
in different families. To account for these data, it has been proposed that
gene dosage may play an important role in the cause of WS, with patients
having a lower effective dose of
PAX3
exhibiting more severe phenotypes.
Waardenburg patients with a milder series of melanocyte defects have
mutations in the transcription factor
MITF
(Tassabehji et al. 1994). MITF
has been shown to transcriptionally transactivate the gene for tyrosinase, a
key enzyme in melanogenesis and overexpression of MITF can convert
fibroblasts into cells with melanocyte characteristics (Tachibana et al. 1996).
Defects in
MITF
likely lead to anomalies during melanocyte differentiation
which cause the hearing defects and hypopigmentation seen in WS type 2
patients.
Only recently has the role of MITF in melanocyte differentiation been
integrated into the phenotypes seen in patients with
PAX3
mutations.
PAX3 can transcriptionally transactivate the
MITF
promoter (Watanabe et
al. 1998). These results suggest that PAX3 directly regulates
MITF
, and that
MITF
, as a gene that requires functional PAX3 for expression, is responsi-
ble for the defects seen in melanocyte differentiation in WS types 1 and 3.
These studies provide the first example of the cascade of transcription
factors required for inner ear development.
So far, over eight transcription factors, each a member of a distinct
transcription-factor family, have been identified as key players in the regu-
lation of genes required for inner ear development. In most cases, the genes
regulated by the transcription factors have not been precisely identified.
Ultimately, these downstream genes are required for both the development
