Biology Reference
In-Depth Information
in the stria vascularis (Cosgrove et al. 1996). Similar studies of the guinea
pig demonstrated that expression of these three chains was limited to the
tectorial and basilar membranes (Kalluri et al. 1998). This discrepancy in
expression patterns could be due to interspecies differences, or technical
variations in experimental protocol. If interspecies differences do exist, it
will be even more important to determine expression patterns for the
human cochlea. Accurate knowledge of these expression patterns is impor-
tant, since it provides a conceptual foundation for correlating Alport syn-
drome genotypes with auditory system phenotypes.
5.5.4 Animal Models of Alport Syndrome
The auditory and renal phenotype of a
Col4a3
-/- knock-out mouse is very
similar to that observed in human patients with Alport syndrome (Cosgrove
et al. 1996). ABR analyses of
Col4a3
-/- mice demonstrated small increases
in thresholds across all frequencies at six to eight weeks of age (Cosgrove
et al. 1998). The cochlear basement membranes in
Col4a3
-/- mice were
either thin or absent, except in the stria vascularis, where they were signif-
icantly thickened (Cosgrove et al. 1998). This latter change was similar to
the basement membrane changes observed in the glomeruli of Alport syn-
drome kidneys, and was associated with marked endothelial cell swelling
and decreased capillary lumen size (Cosgrove et al. 1998). Furthermore, in
severe cases the marginal cells of the stria exhibited pathologic changes,
suggesting that perhaps the primary auditory defect may be an altera-
tion of strial function and homeostasis. Alternatively, basement mem-
brane changes in the basilar membrane may affect its stiffness and sound-
transduction properties. However, the relevance of either model is unclear,
since minimal hearing loss was observed in the mutant mice (Cosgrove
et al. 1998). The reason for this lack of severe hearing loss in
Col4a3
-/-
mice may also underlie the reduced penetrance of sensorineural hearing
loss in human patients with Alport syndrome. It is possible that other loci
are modifying the auditory phenotype in
Col4a3
-/- mice. This hypo-
thesis may be addressed by breeding the mutant line on other strain back-
grounds. Identification and characterization of these modifying loci, as
well as other mouse strains with
Col4a4
or
Col4a5
null mutations, will
shed more light on the development of sensorineural hearing loss in Alport
syndrome.
5.6 Jervell and Lange-Nielsen Syndrome
5.6.1 Phenotype
Jervell and Lange-Nielsen syndrome (OMIM 220400) is an autosomal
recessive disorder consisting of profound congenital sensorineural hearing
loss in combination with sudden fainting attacks and a cardiac conduc-
tion abnormality characterized by a prolonged Q-T interval on an electro-
