Cadherin-23 mutations cause calcium-dependent, allele-sensitive mechanosensory defects

Area of Science:

• Molecular Biology
• Biophysics
• Genetics

Background:

• Point mutations in tip-link proteins are linked to hereditary hearing loss.
• Many mutations are distal, not affecting protein binding interfaces, and do not impact balance or vision.

Purpose of the Study:

• To investigate how distal mutations in tip-link proteins affect mechanical structure and function.
• To understand the mechanism behind selective impairment of hearing while sparing vestibular and retinal function.

Main Methods:

• Protein engineering of wild-type and mutant tip-link complexes.
• Single-molecule force spectroscopy to analyze mechanical properties.
• Molecular dynamics simulations to examine structural alterations.

Main Results:

• Mutations subtly alter folding kinetics and force-dependent rupture behavior of tip-link complexes.
• Mechanical alterations are more pronounced under low calcium conditions, mimicking the cochlea.
• These effects are attenuated at higher calcium concentrations, consistent with vestibular and retinal environments.

Conclusions:

• Distal mutations can compromise tip-link function in a calcium-sensitive manner.
• This provides a mechanistic explanation for selective hearing impairment in hereditary deafness.
• Findings highlight the role of mechanical properties and calcium sensitivity in auditory function.