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From the Divisions of Pathology*
and
Otolaryngology,
Hospital for Sick Children and
University of Toronto, Toronto, Canada; the Department of
Pathobiology,||
University of Guelph, Guelph, Canada; the
Divisions of Immunology
and
Ultrastructural Biology,
Shigei
Medical Research Institute, Okayama, Japan; and the Department of
Molecular Biology and Biochemistry,¶
Okayama
University Medical School, Okayama, Japan
Alport syndrome is an inherited disorder of type IV collagen with
progressive nephropathy, ocular abnormalities, and
high-tone sensorineural deafness. In X-linked Alport syndrome,
mutations in the COL4A5 gene encoding the 
5 chain of
type IV collagen lead to loss of the 3/4/5 network and
increased susceptibility of the glomerular basement membrane to
long-term damage. The molecular defects that underlie the otopathology
in this disease remain poorly understood. We used a canine model of
X-linked Alport syndrome to determine the expression of type IV
collagen -chains in the inner ear. By 1 month in normal adult
dogs, the 3, 4, and 5 chains were
co-expressed in a thin continuous line extending along the basilar
membrane and the internal and external sulci, with the
strongest expression along the lateral aspect of the spiral ligament in
the basal turn of the cochlea. Affected dogs showed complete absence of
the 3/4/5 network. The lateral aspect of the spiral ligament
is populated by tension fibroblasts that express -smooth muscle
actin and nonmuscle myosin and are postulated to generate radial
tension on the basilar membrane via the extracellular matrix for
reception of high frequency sound. We propose that in Alport
syndrome, the loss of the 3/4/5 network eventually
weakens the interaction of these cells with their extracellular
matrix, resulting in reduced tension on the basilar membrane
and the inability to respond to high frequency sounds.
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