The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention
Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz
Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz
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Research Article Development Otology

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Abstract

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Authors

Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz

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Figure 6

Marginal cell morphology and permeability of vascular barrier in Ndp-KO stria vascularis.

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Marginal cell morphology and permeability of vascular barrier in Ndp-KO ...
(A–D) Anti-ZO1 immunostaining demonstrates evenly sized marginal cells at 1 month in the WT (A) and Ndp-KO (B) lateral wall; n = 3 WT, n = 4 Ndp-KO. At 2 months, WT marginal cells remain evenly sized (C), while those in Ndp-KO (D) are unevenly sized; n = 3 WT, n = 3 Ndp-KO. (E–L) Permeability assessments at P20 and 1 and 2 months using a fluorescent tracer assay (green, FITC-BSA; blue, vessels counterstained for endomucin). (E–J) FITC-BSA is restricted within the vessels (arrowheads) in WT, but detectable outside them in Ndp-KO (arrows). (K and L) At 2 months, FITC-BSA signal is uneven in Ndp-KO stria with patches of weak (arrowheads) and strong (arrows) intensity. Scale bars: 30 μm (A–D), 50 μm (E–J), 500 μm (K and L). (M) Extravascular FITC intensity is elevated in Ndp-KO compared with WT (2-way ANOVA; Šidák’s post hoc test showed P < 0.05 at P20; see also Supplemental Figure 5). Mean ± SD is represented; n = 3 WT, n = 3 Ndp-KO at 1 and 2 months. (N–P) Quantitative reverse transcriptase PCR analyses of vascular barrier and permeability marker gene expression. In Ndp-KO cochlea, Cldn5 expression was significantly reduced from P20 (N), but Plvap and Cav1 increased progressively from 1 and 2 months, respectively (O and P), compared with WT. Normalized fold change ± SD; 2-way ANOVA with Šidák’s post hoc test. n = 6 WT, n = 3 KO at P10; n = 7 WT, n = 6 KO at P20; n = 8 WT, n = 6 KO at 1 month; n = 6 WT, n = 7 KO at 2 months. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.