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profound levels at high frequencies. The type 3 phenotype includes pro-
gressive hearing loss with variable onset of retinitis pigmentosa.
5.4.2 Genetics of Usher Syndrome
Autosomal recessive inheritance has been well established for Usher
syndrome. There is significant genetic heterogeneity, with six genetically
mapped loci for type 1 (
USH1A
,
USH1B
,
USH1C
,
USH1D
,
USH1E
,
and
USH1F
), two loci for type 2 (
USH2A
,
USH2B
), and one locus for
type 3 (
USH3
; see Fig. 6.1 and Table 6.5). Moreover, in other families the
Usher syndrome phenotype is not linked to any of these known loci, indi-
cating the existence of additional Usher syndrome loci (Pieke-Dahl et al.
1998).
5.4.2.1 Usher Syndrome Type IB is Caused by Mutations in Myosin VIIA
Two Usher syndrome loci have now been identified (Table 6.5). The first
Usher syndrome locus (
USH1B
) to be cloned was
MYO7A
on chromosome
11q13.5, encoding unconventional type VII myosin (see section 3.10) (Weil
et al. 1995). Identification of
MYO7A
as the
USH1B
gene was facilitated
by the recognition of a mouse deafness mutant,
shaker 1
(
sh-1
), as a pos-
sible mouse orthologue. Although
sh-1
does not have retinal degenera-
tion, the human nonsyndromic deafness locus
DFNB2
was also known to
map to the same region as
USH1B
(Guilford et al. 1994b), and therefore
sh-1
could be the mouse orthologue of
DFNB2
and
USH1B
. Gibson et al.
(1995) identified mutations in a novel mouse gene encoding an uncon-
ventional myosin,
Myo7a
, associated with the
sh-1
phenotype (see Section
3.10).
Weil et al. (1995) then examined
USH1B
families for
MYO7A
mutations.
Five mutations were found that were all in the motor domain and predicted
to result in functional null alleles. Subsequent studies have described muta-
tions distributed across all of the major
MYO7A
domains (Adato et al.
1997; Levy et al. 1997; Liu et al. 1998; Liu et al. 1997a; Liu et al. 1997b; Liu
et al. 1997c; Weil et al. 1995; Weil et al. 1997; Weston et al. 1996) (Fig. 6.4).
Liu et al. (1998) extended the known phenotypic spectrum associated with
MYO7A
by demonstrating compound heterozgous mutations in two
affected siblings with an atypical Usher syndrome phenotype most closely
related to that of Usher syndrome type 3.
The discovery of myosin VIIA mutations in Usher syndrome type 1B has
provided new insights and raised new questions about unconventional
myosins and their function within the sensory neuroepithelium of the inner
ear (Gillespie et al. 1996; Hasson 1997). Unconventional myosins are
known to be motor proteins that move along actin filaments in an ATP-
dependent manner. Their tails are thought to associate with different
macromolecular structures that are moved in relation to the actin network.
Myosin VIIa has been localized to the crosslinks of adjacent stereocilia in
hair cells, suggesting that myosin VIIa may be important for maintenance
