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regating hereditary hearing loss which is not linked to known phrasing
hearing loss loci.
(3) There are now two examples of mutations of the same gene that
cause both syndromic and nonsyndromic hearing loss. Alleles of
MYO7A
(
DFNB2, DFNA11
) are associated with nonsyndromic sensorineural
hearing loss, as well as type 1B and atypical Usher syndrome phenotypes
(Liu et al. 1998) (see Section 5.4). Moreover, mutations of
PDS
can cause
Pendred syndrome, as well as nonsyndromic recessive deafness,
DFNB4
(see Section 5.2). A cytogenetic map of nonsyndromic and syndromic loci
associated with hearing loss is shown in Figure 6.1. When the genetic map
locations for a nonsyndromic hearing loss locus and a syndromic hearing
loss locus overlap, it is worth considering the possibility that different alleles
of the same gene may be responsible for both forms of hereditary hearing
impairment.
(4) There are also both dominant and recessive mutant alleles of
GJB2
,
MYO7A
and
TECTA
. The historical distinction between DFNA and DFNB
loci will probably continue to grow more obscure as additional alleles of
these genes are identified. “Dominance and recessiveness are not proper-
ties of genes per se but the result of the action of the genetic locus in ques-
tion...”(Rieger et al. 1991).
(5) Two of the six DFNB loci identified so far,
DFNB2
and
DFNB3
,
encode unconventional myosins
MYO7A
and
MYO15
, respectively. The
functions of these two molecular motors in the auditory system, as well as
those encoded by
MYO6
(Avraham et al. 1995) and
MYO1
(Gillespie and
Corey 1997), are actively being studied, but remain enigmatic.
(6) Mouse hearing loss loci have been instrumental in identifying the
human orthologues. The identification of the mouse
shaker1
and
shaker2
genes greatly facilitated the identification of
DFNB2
and
DFNB3
, respec-
tively. Saturation mutagenesis screens and mapping studies of new hearing
loss mutations in the mouse should further accelerate discovery of the
human counterparts. Moreover, once a human gene for hearing loss is
identified, the mouse provides an excellent model system for studying the
spatial and temporal expression profiles of these genes, as well as the phe-
notypic effects of the corresponding mouse mutations (Steel and Bock
1983).
(7) With the exception of
DFNB1
(
GJB2
), for which epidemiological
data is emerging, little is known about the contribution made by each DFN,
DFNA, and DFNB locus to hereditary hearing loss worldwide.
b
4. Otosclerosis
Otosclerosis (MIM 166800) is a common cause of hearing loss in the adult
Caucasian population. It is characterized by one or more histologic foci
of progressive endochondral bone sclerosis within structures of the otic
