The inner ear of dogs with X-linked nephritis provides clues to the pathogenesis of hearing loss in X-linked Alport syndrome

Alport syndrome is an inherited disorder of type IV collagen with progressi ve nephropathy, ocular abnormalities, and high-tone sensorineural deafness. in X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alp ha5 chain of type IV collagen lead to loss of the alpha3/alpha4/alpha5 netw ork and increased susceptibility of the glomerular basement membrane to lon g-term damage. The molecular defects that underlie the otopathology in this disease remain poorly understood. We used a canine model of X-linked Alpor t syndrome to determine the expression of type IV collagen alpha -chains in the inner ear. By I month in normal adult dogs, the alpha3, alpha4, and al pha5 chains were co-expressed in a thin continuous line extending along the basilar membrane and the internal and external sulci, with the strongest e xpression along the lateral aspect of the spiral ligament in the basal turn of the cochlea. Affected dogs showed complete absence of the alpha3/alpha4 /alpha5 network. The lateral aspect of the spiral ligament is populated by tension fibroblasts that express alpha -smooth muscle actin and nonmuscle m yosin and are postulated to generate radial tension on the basilar membrane via the extracellular matrix for reception of high frequency sound. We pro pose that in Alport syndrome, the loss of the alpha3/alpha4/alpha5 network eventually weakens the interaction of these cells with their extracellular matrix, resulting in reduced tension on the basilar membrane and the inabil ity to respond to high frequency sounds.