# Integrative Structural and Functional Characterization of Tip-Link Cadherins Deafness

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $648,310

## Abstract

Deafness is a major health problem. A major cause of deafness is defects in hair cells, the mechanosensory
cells of the cochlea that convert sound induced vibrations into electrical signals to provide our sense of
hearing. Mutations in the genes encoding protocadherin (PCDH15) and cadherin 23 (CDH23) cause hearing
loss. Both genes are expressed in the hair bundles of the mechanosensory hair cells of the inner ear where
they form heterophilic adhesion complexes that are important for hair bundle morphogenesis and
mechanotransduction. Significantly, different mutation in both PCDH15 and CDH23 lead to different disease
outcomes. While some mutations cause profound congenital deafness with retinal impairment (Usher
Syndrome) others lead to recessive and progressive hearing loss without visual involvement. Gene-association
studies also suggest a link of CDH23 polymorphisms with age- and noise-induce hearing loss. The
mechanisms by which different mutations lead to distinct disease outcomes are poorly defined. We propose
here to combine high-resolution structural studies with functional studies in hair cells to gain insights into the
mechanisms by which PCDH15 and CDH23 regulate hair cell function and to define disease mechanisms. To
achieve this goal, a laboratory with expertise in studying the biophysical and structural properties of cadherins
and a laboratory dedicated to the study of auditory neuroscience have combined their efforts to achieve what
either could not accomplish alone. Unlike previous studies that have focused on structural analysis of small
monomeric fragments of CDH23 and PCDH15 expressed in bacteria, the team proposed to define the high-
resolution structure of natively assembled PCDH15-CDH23 complexes using crystallography and cryo-EM.
Structural data will be validated biochemically and by functional interrogation of mutant cadherins in the
physiologically relevant mechanosensory hair cells paying attention to mutations associated with disease. We
anticipate that our studies will provide the first high-resolution native structure of any protein complex important
for mechanotransduction and provide mechanistic insights into its functional properties and pathophysiological
mechanisms that are associated with different forms of hearing impairment.

## Key facts

- **NIH application ID:** 9880285
- **Project number:** 5R01DC016960-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ulrich Mueller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $648,310
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880285

## Citation

> US National Institutes of Health, RePORTER application 9880285, Integrative Structural and Functional Characterization of Tip-Link Cadherins Deafness (5R01DC016960-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880285. Licensed CC0.

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