Biology Reference
In-Depth Information
these mutations were critical to identification of the corresponding human
genes in Waardenburg syndrome. Interestingly, auditory function analyses
of
Splotch
(
Sp/
+) mutant mice demonstrate that they do not have hearing
impairment (Steel and Smith 1992). This may be due to the type and
position of the
Splotch
mutation in
Pax3
, or to the effect of other modify-
ing genes with alleles that functionally differ between different mouse
strains (Steel and Smith 1992). A lack of significant correlation of
PAX3
genotype with the presence of hearing loss in WS1 supports the latter
hypothesis (DeStefano et al. 1998). Furthermore, the influence of modify-
ing factors is strongly indicated by the low penetrance and highly variable
expressivity of the WS phenotype, and the observation that hearing loss
is non-randomly distributed among families segregating WS1 (Morell et al.
1997). Moreover, Asher et al. (Asher et al. 1996) described a dissection of
genetic modifiers of expression of the
Pax3
-associated phenotype in
Splotch
mice. They presented evidence that there are at least two modifying loci,
one of which is probably X-linked and the other autosomal. In comparison
with human families, an animal model such as
Splotch
should simplify
the identification of loci modifying
PAX3
mutant phenotypes. This illus-
trates how characterization of genes underlying monogenic traits is estab-
lishing the foundation for identification of modifying loci in complex
multigenic traits. Genetic dissection of multigenic traits is becoming an
increasingly important and immediate challenge facing human geneticists
because most traits and diseases are not usually monogenic, including many
phenotypes of immense public health importance such as hypertension and
atherosclerosis.
5.4 Usher Syndrome
5.4.1 Phenotype
Usher syndrome is an autosomal recessive disorder comprising sen-
sorineural hearing loss and retinitis pigmentosa, a noninflammatory pro-
gressive degeneration of the retina eventually leading to blindness. Usher
syndrome accounts for approximately 3 to 6% of congenital profound deaf-
ness in children, and 50% of the deaf-blind population (Vernon 1959).
Usher syndrome is clinically and genetically heterogeneous. There are
three well established clinical subtypes of Usher syndrome based upon the
onset of retinitis pigmentosa, the severity and onset of hearing loss, and the
presence or absence of peripheral vestibular function (Smith et al. 1994).
The Usher syndrome type 1 phenotype is congenital profound hearing loss
with prepubertal onset of retinitis pigmentosa, and absent peripheral
vestibular responses. The type 2 phenotype is congenital stable severe
hearing loss with postpubertal onset of retinitis pigmentosa, and normal
peripheral vestibular function. The typical audiometric pattern of type 2 is
a mild low-frequency sensorineural hearing loss down-sloping to severe or
