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of the structural integrity of hair cell bundles (Hasson et al. 1997). This pos-
tulated role for myosin VIIa is consistent with the observed histopathologic
changes described for Usher syndrome (Belal 1975; Cremers and Delleman
1988; Shinkawa and Nadol 1986; van Aarem et al. 1995) and the
shaker 1
mouse (Shnerson et al. 1983).
5.4.2.2 Identification of the USH2A Gene
A second gene for Usher syndrome was recently described by Eudy et al.
(1998). They used positional cloning methods to identify an open reading
frame at the
USH2A
locus on chromosome 1q41. The corresponding cDNA
was sequenced and analyzed for mutations in type 2 Usher syndrome
patients who showed linkage to 1q. Heteroduplex analyses detected three
different frameshift mutations that segregated with the Usher type 2 phe-
notype. These mutations were all predicted to cause premature chain
termination and result in functional null alleles.
USH2A
expression was
detected in human fetal cochlea, eye, brain and kidney, and in adult retina.
The central one-third of the
USH2A
gene has ten laminin epidermal growth
factor motifs arranged in tandem, which are similar to those of laminins.
Laminins are extracellular proteins known to be important for cell adhe-
sion.
USH2A
also has four tandem repeats of a fibronectin type III motif
in the carboxy terminal region. Sequence analysis predicts an amino ter-
minal signal peptide, at least two transmembrane domains, and 18 poten-
tial glycosylation sites (Eudy et al. 1998). The presence of these motifs
suggests a role for the
USH2A
protein in the extracellular matrix or cell
adhesion.
5.4.3 Animal Models of Usher Syndrome Type IB
There are at least seven different known alleles of
sh-1
, which are associ-
ated with
Myo7a
mutations. Gibson et al. (1995) analyzed a portion of
Myo7a
for mutations in the seven known
sh-1
alleles and found three muta-
tions in the head region, all of which are predicted to result in null alleles.
Mutations in the other four alleles have subsequently been identified, and
all seven mutations are predicted to cause loss-of-function (Mburu et al.
1997). The observed pattern of neuroepithelial degeneration in
sh-1
mice
and the localization of myosin VIIa to cross-links of adjacent stereocilia in
hair cells implicate myosin VIIa in the maintenance of stereocilia integrity
in the inner ear sensory epithelium (Hasson et al. 1997; Shnerson et al.
1983).
5.5 Alport Syndrome
5.5.1 Phenotype
The combination of hereditary sensorineural hearing loss with progressive
nephritis known as Alport syndrome (OMIM 301050, 203780) accounts for
