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 8

Abnormal pericyte coverage of capillaries in the lateral wall affecting the spiral ligament and stria vascularis.

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Abnormal pericyte coverage of capillaries in the lateral wall affecting ...
(A–V) Stria vascularis (SV) (A–H) and spiral ligament (SL) capillaries (I–V), immunostained with vessel marker anti-endomucin (Emcn), pericyte marker anti-desmin (Des), and vascular tight junction marker anti–claudin-5 (Cldn5) antibodies. (A and E) At P10, pericytes (Des, white) are evenly distributed across the SV (Emcn, blue) in both WT (A) and Ndp-KO (E). (B–H) At 2 months, Ndp-KO strial capillaries (F–H) are either high-endomucin, low–claudin-5, low-pericyte-coverage vessels (white arrows, F–H) or low-endomucin, high–claudin-5, dense-pericyte-coverage vessels (red arrows, F–H), compared with the even staining patterns of WT strial capillaries (B–D). Scale bars in A–H: 30 μm. (I–O) At P10 and 2 months, WT SL capillaries (I–K) form regular branches (Emcn, I, J, and N) with even pericyte coverage (desmin, K, L, and N; white) and claudin-5 staining (M; cyan). J and K are a higher magnification of I. (P–V) In contrast, Ndp-KO SL capillaries are abnormal from P10, showing either irregular patterns of high-endomucin-staining meshworks (P, white arrows) with filopodia (Q, yellow arrows) and low pericyte coverage (R: Des, white; white arrows), or, alternatively, low endomucin staining (P–T, red arrows) and abnormally dense pericyte wrapping (R and U: Des, white; red arrows). Q and R are a higher magnification of P. Like in the SV, abnormal vessels with high pericyte coverage show claudin-5 (V, red arrow), whereas vessels loosely covered with pericytes show low or absent claudin-5 (V, white arrows), compared with the pattern in WT (N and O). Scale bars in I–V: 100 μm (I and P), 20 μm (all others). n = 9 WT, n = 8 Ndp-KO analyzed at P10, and n = 14 WT, n = 15 Ndp-KO analyzed at 2 months, for desmin/endomucin/claudin-5 costaining.