# Usher Proteins in the Inner ear Structure and Function

> **NIH DC R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2026 · $622,550

## Abstract

Hearing loss (HL) is an etiologically diverse condition that can occur at any age and severity level, affecting 1 in
500 infants and more than 360 million people globally1; 2. In numerous ethnicities, we have previously identified
pathogenic variants in the CIB2 gene encoding Calcium and Integrin-Binding protein 2 (CIB2) as the etiology of
HL4-6. In past funding periods, we discovered that CIB2 is expressed in the mouse hair cell stereocilia and binds
to the TMC1 and TMC2 components of the hair cell MET complex, and that deafness-causing CIB2 mutations
disrupt these interactions. We concluded that CIB2 is essential for the MET function7. We also generated two
mouse models carrying the human deafness-related Cib2 variants (Cib2F91S and Cib2R186W knock-ins) and
characterized them together with a mouse line lacking CIB2 (Cib2ko). We found that Cib2F91S and Cib2ko mouse
strains are deaf and lack typical MET responses in the auditory hair cells, despite the existence of tip links that
are ordinarily responsible for gating the MET channels. In contrast, the p.R186W mutation does not disrupt the
interaction between CIB2 and TMC1/27, and MET currents in mutant mice are diminished but still detectable. It
is particularly intriguing that CIB2's participation in the MET machinery may be responsible for at least some of
the several well-known effects of Ca2+ on hair cell mechanotransduction. Here, we will investigate the precise
function of CIB2 in MET. We hypothesize that CIB2 is a calcium-dependent element that regulates sensitivity of
the MET channels and force transmission to these channels in the mammalian auditory hair cells of. Our findings
further determined that CIB2 deficiency causes an overgrowth of transducing shorter row stereocilia in the hair
bundle without altering the non-transducing tallest row stereocilia7. This observation cannot be explained solely
by the loss of mechanotransduction, since blockage of the MET channels causes an opposite effect, the
retracti

## Key facts

- **NIH application ID:** 11229634
- **Project number:** 5R01DC012564-14
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Zubair M. Ahmed; Gregory I Frolenkov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DC
- **Fiscal year:** 2026
- **Award amount:** $622,550
- **Award type:** 5
- **Project period:** 2012-12-01T00:00:00 → 2028-11-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11229634

## Citation

> US National Institutes of Health, RePORTER application 11229634, Usher Proteins in the Inner ear Structure and Function (5R01DC012564-14). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11229634. Licensed CC0.

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