Distribution of Type IV Collagen in the Cochlea in Alport Syndrome

Abstract

To determine the distribution of ␣1, ␣3, and ␣5 chains of type IV collagen in the cochlea in Alport syndrome.Design: Case-control study.Patients: Two patients with sensorineural hearing loss due to Alport syndrome. Both patients had known mutations in the COL4A5 gene.Main Outcome Measures: Immunostaining was used to study the distribution of type IV collagen (␣1, ␣3, and ␣5 chains) within the cochlea. Immunostaining was also performed in the cochlear tissues of an unaffected individual used as a control.Results: In the control ear, ␣1 staining was observed in the basement membrane overlying the basilar mem-brane, in the basement membrane of cochlear blood vessels and Schwann cells, and within the spiral limbus. In the control ear, we also observed strong staining for ␣3 and ␣5 chains in the basement membrane overlying the basilar membrane and within the spiral ligament. In both cases with Alport syndrome, no immunostaining was observed for ␣3 or ␣5 chains within the cochlea, whereas ␣1 staining was present in locations similar to that seen in the control ear. Conclusions:The results indicate that isotype switching does not occur within the cochlea in Alport syndrome. The results are also consistent with the hypothesis that the sensorineural hearing loss in Alport syndrome may be due to alterations in cochlear micromechanics and/or dysfunction of the spiral ligament.

Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel COL4A6 variants

“…These abnormalities are likely to result in compromised basement membrane integrity within the inner ear, which can disrupt the structural support and signaling functions of the cochlear basement membranes ultimately impairing hair cell function and contributing to sensorineural HL. 26 Our results are consistent with previously reported cases ( Supplementary Table S2 ). In the originally described Hungarian family, the COL4A6 c.1771G>A p.(Gly591Ser) variant led to prelingual, bilateral, severe sensorineural HL and cochlear malformations with incomplete separation of the cochlea in hemizygous males, while heterozygous females showed milder, variable HL in adulthood.…”

Vestibular and audiological findings in the Alport syndrome

“…The first is a basement membrane separation from the cells of the organ of Corti. A structurally defective basement membrane may provide inadequate adhesion support between the cells of the organ of Corti and the basilar membrane so that basilar membrane motion is not properly "tuned" by the outer hair cells (Merchant et al, 2004;Ungar et al, 2018;Zehnder et al, 2005). This hypothesis is consistent with our clinical observations that speech discrimination remains excellent in AS and that otoacoustic emissions are absent in ears with hearing loss because of dysfunctional outer hair cells.…”

“…In the study by Kleppel, Santi, Cameron, Wieslander, and Michael (1989), α1 chains of collagen IV were observed in all of the basement membranes, whereas the α3 and α4 chains were only found within the basement membrane over the basilar membrane. Zehnder et al (2005) confirmed Kleppel's findings and demonstrated the presence of α3 and α5 chains also within the spiral ligament and the spiral limbus The authors studied the distribution of collagen IV in the cochlea of two patients with sensorineural hearing loss due to AS: the distribution of α1 chains was similar to that seen in normal ears, whereas both the α3 and α5 chains were absent.…”

A Novel Heterozygous Mutation of theCOL4A3Gene Causes a Peculiar Phenotype without Hematuria and Renal Function Impairment in a Chinese Family

“…Zehnder et al discovered that in human cochlea, the α 3 chain is specifically expressed in collagen bundles in the basement membrane, spiral ligament, and spiral margin. These results suggest that hearing loss may be due to cochlear micromechanical changes or are consistent with the helical ligament dysfunction hypothesis [2]. Type IV collagen α 3 chains are also found in the basement membranes of the conjunctiva, cornea, iris, lens capsule, and Descemet's and Bruch's membrane [33].…”