ULTRASTRUCTURAL, PHYSIOLOGICAL, AND MOLECULAR DEFECTS IN THE INNER-EAR OF A GENE-KNOCKOUT MOUSE MODEL FOR AUTOSOMAL ALPORT-SYNDROME

The cochleae from a COL4A3-deficient mouse line were examined for defe cts that might shed light on the molecular mechanism of otopathology o bserved in humans with Alport syndrome. At the light microscopic level no obvious defects were observed. Immunohistochemical analysis using antibodies specific for the basement membrane collagen chains revealed the absence of the COL4A3 and COL4A4 chains throughout the membranous labyrinth. The COL4A5 chain was absent from all cochlear basement mem branes except those in the vessels of the stria vascularis. Expression of the COL4A1 and COL4A2 chains was unchanged in the mutant. Electron microscopic examination of the cochlear basement membranes revealed s ignificant thinning of the basement membrane running from the spiral l imbus, down the inner sulcus, across the basilar membrane and up to th e spiral prominence. Basement membranes that normally ensheathe the ro ot cells were not detectable. In contrast, the basement membranes surr ounding the vessels of the stria vascularis were significantly thicken ed in the mutant. This was associated with endothelial cell swelling a nd a marked decrease in internal capillary diameter. In severe cases, pathology was observed in the marginal cells with a loss of basolatera l infoldings. Immunohistochemical analysis of the strial vessels revea led an increase in entactin and collagen COL4A1 and COL4A2 chains. Aud itory-evoked brainstem response measurements suggest a small increase in thresholds across all frequencies when successive measurements on i ndividual mutant mice were examined between 6 and 8 postnatal weeks. C ombined, these results illustrate changes in the basement membranes of the strial vessels that bear resemblance to Alport glomerular basemen t membrane pathology. A closer look at this compartment in human Alpor t biopsy specimen may be warranted. (C) 1998 Elsevier Science B.V. All rights reserved.