Biology Reference
In-Depth Information
genetic deafness have been shown to involve two members of the
POU
domain family of transcription factors (Griffith and Friedman, Chapter 6).
This gene family was originally discovered in studies aimed at understand-
ing how functionally distinct cell types arise within the pituitary gland.
Many members of this family are expressed in fetal brain, including the
neural tube and otic vesicle. De Kok et al. (1995) showed that the syndrome
of X-linked congenital fixation of the stapes footplate with perilymphatic
gusher (
DFN 3
) was caused by mutations in the
POU3F4
gene at Xq13.
Mutations at this locus also lead to characteristic morphologic abnormali-
ties in the internal auditory meatus, which can be detected by radio imaging
and may contribute to the pathogenesis of the neurosenory component of
the hearing loss. Mutations at a second locus
POU4F3
on 5q31 have been
shown to be the cause of an autosomal-dominant form of hearing loss,
DFNA15
(Vahava et al. 1998). The expression of this gene is restricted
almost exclusively to the fetal cochlea and knockouts of the murine
homolog result in complete absence of the hair cells, with subsequent loss
of the cochlear and vestibular ganglia cells. It seems likely that the gene
must play some role in sustaining the hair cells, as well as initiating their
differentiation in view of the progressive nature of the hearing loss in
affected family members.
DFNA7
, a dominantly inherited form of pro-
gressive high-frequency hearing loss, was mapped to 1q21-q23 by Fager-
heim et al. (1996). As noted by the authors, this region includes another
member of the
POU
gene family,
POU2F1
that is also expressed in the
embryonic cochlea of the rat.
4.2 Homeostasis
The high potassium concentration of the cochlear endolymph is a unique
feature of the physiology of the ear, upon which health and normal func-
tion of the hair cells is dependent. An influx of potassium ions through
gated potassium channels is required for transducing physical deflections
of the hair cells into nerve impulses that can be processed and transmitted
for subsequent neural processing. Several forms of genetic deafness now
seem to have as a common denominator a defect in the maintenance of this
critical potassium gradient. In the autosomal recessive Jervell and Lange-
Nielsen syndrome, the defect involves one of at least two genes that code
for proteins required to form normal potassium channels in the heart as
well as the cochlea (Splawski et al. 1997; Duggal et al. 1998). In the heart,
expression of the mutant genes leads to a characteristic prolongation of the
QT interval, and a predisposition to syncopal attacks and sudden death.
Heterozygotes for mutations at the
KVLQT1
locus on 11p15.2 and the
KCNE1
locus on 21q22.1 may exhibit the cardiovascular component of
the syndrome without hearing loss. This dominantly transmitted pheno-
type, Ward-Romano syndrome, can also be caused by mutations involving
other ion-channel genes (Wattanasirichaigoon and Beggs 1998). Whether
