Biology Reference
In-Depth Information
et al. 1996). In addition, heterozygous
EDN3
mutations have also been
demonstrated in isolated Hirschsprung disease (Bidaud et al. 1997).
WS4 may also be caused by heterozygous mutations in
SOX10
(Pingault
et al. 1998), encoding the transcription factor SRY-box 10. The mouse
homologue,
Sox10
, was first identified as the causative gene in the mouse
mutant dominant megacolon (
dom
) (Herbarth et al. 1998; Southard-Smith
et al. 1998), which results in a Hirschsprung-like phenotype in conjunction
with coat color spotting. Based upon the similarity of the
dom
and WS4
phenotypes, and expression of
Sox10
in neural crest structures, Pingault
et al. (Pingault et al. 1998) examined the role of
SOX10
in WS4. They
found four mutations, all of which predicted to cause loss-of-function
and haploinsufficiency. These findings suggest a relationship between the
EDN3/EDNRB
signaling system and
SOX10
, which has yet to be delin-
eated. They also suggest a relationship of these genes to
PAX3
and
MITF
.
It is possible that
EDN3
,
EDNRB
, or
SOX10
mutations may account for
cases of WS1 or WS2 that do not have
PAX3
or
MITF
mutations. However,
no such mutations have been reported to date (Read and Newton 1997),
and it seems likely that other gene loci are associated with Waardenburg
syndrome.
5.3.3 Pathogenesis of Hearing Loss in Waardenburg Syndrome
The genetic data have given some clues to the molecular basis of sen-
sorineural hearing loss in Waardenburg syndrome. At least one cause of
auditory dysfunction is aberrant development of those cells composing the
intermediate layer of the stria vascularis that are derived from neural crest
precursors. This was predicted by histopathologic studies of temporal bones
from humans with Waardenburg syndrome demonstrating strial atrophy.
Although it is often difficult to discern primary neuroepithlelial from
cochleosaccular degeneration in human temporal bone specimens (Smith
et al. 1992), the differing patterns of neuroepithelial degeneration in the
Waardenburg syndrome specimens were most likely secondary to strial dys-
function with loss of the endocochlear potential (Fisch 1959; Nakashima
et al. 1992; Rarey and Davis 1984; Steel et al. 1987). It is also possible that
the hearing loss of Waardenburg syndrome may have a digenic etiology in
at least some cases (Balciuniene et al. 1998; Chen et al. 1997; Morell et al.
1997). According to this model, auditory dysfunction would be observed
with strial dysfunction due to heterozygous
PAX3
or
MITF
mutations in
combination with a mutant allele at another locus. These hypotheses may
now be tested in animal models, such as the multiple mouse mutant models
for Waardenburg syndrome that are available.
5.3.4 Animal Models of Waardenburg Syndrome
There is already at least one mouse mutant line available for each of
the genes implicated in Waardenburg syndrome (Table 6.5). Several of
