A Histologic Study of Nonmorphogenetic Forms of Hereditary Hearing Impairment

Smith, Richard J.H.; Steel, Karen P.; Barkway, Chris; Soucek, Sava; Michaels, L.

doi:10.1001/archotol.1992.01880100077016

Cited by 18 publications

(5 citation statements)

References 35 publications

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“…This thickened basement membrane phenotype in the Alport mouse confirmed what Wiedauer and Arnold reported for thickened capillary basement membrane in cochleas of Alport patients (61). However, more recent human Alport studies have revealed a normal stria vascularis structure but the presence of a zone of separation between basilar membrane and overlying cells of the organ of Corti, as well as partially torn Reissner's membrane (19)(20)(21)(22). Here we show by EM that OPN deletion ameliorates the thickening of the strial capillary basement membrane of Alport mice, suggesting that OPN deficiency reduces cochlear pathology in Col4a3 -/mice.…”

Section: Discussionsupporting

confidence: 46%

“…Otopathology of Alport syndrome is characterized by high-frequency sensorineural hearing loss and this otopathology is present in the Alport mouse (8). On the other hand, thickened cochlear strial capillary basement membrane has been reported in the Alport mouse (8) but not in Alport patients (19)(20)(21)(22). To examine the effects of OPN deficiency on hearing ability of Alport mice, we recorded the responses to a series of clicks and pure tone (low frequency) stimuli using auditory brainstem response (ABR) tests.…”

Section: Resultsmentioning

confidence: 99%

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Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

Ding¹,

Yousefi²,

Goncalves³

et al. 2018

JCI Insight

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Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr-/- mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.

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Section: Discussionsupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

Ding¹,

Yousefi²,

Goncalves³

et al. 2018

JCI Insight

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“…In the past, temporal bone studies had failed to identify consistent histopathologic abnormalities within the cochlea. [13][14][15][16] Our team's recent study of the otopathologic changes in a series of 9 Results of immunostaining within the cochlea for antibodies against ␣1, ␣3, and ␣5 chains of type IV collagen for the control ear, as well as cases 1 and 2 with Alport syndrome. Expression of ␣1 is similar in the control ear and both cases with Alport syndrome, being present in the basement membrane (BM) overlying the basilar membrane, the BM of blood vessels, and the BM of Schwann cells.…”

Section: Commentmentioning

confidence: 99%

Distribution of Type IV Collagen in the Cochlea in Alport Syndrome

Zehnder¹,

Adams

Santi³

et al. 2005

Arch Otolaryngol Head Neck Surg

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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.

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“…The SNHL generally does not exceed 60 to 70 dB, and speech discrimination scores are usually excellent. Although audiometric studies have suggested a cochlear lesion as being responsible for the HL, 7,8 previous temporal bone studies have failed to identify histopathologic abnormalities that occur in the cochlea in a consistent manner in Alport syndrome 9–12 . Histopathologic abnormalities within the inner ear that have been described include loss of hair cells, loss of cochlear neurons, degenerative changes in the stria vascularis, basophilic deposits within the stria, and endolymphatic hydrops, but none of these changes have been observed consistently or even in a majority of the cases 9–12 …”

Section: Introductionmentioning

confidence: 99%