Jeff Holt, PhD

Department of Otolaryngology and Neurology
Boston Children’s Hospital
(February 27, 2018)

Function, Dysfunction and Restoration of Auditory Sensory Transduction Channels

Hearing, like our other senses, is often taken for granted. It is something the body and brain seem to accomplish without effort. In reality, cells within the inner ear, the hair cells, convert sound information into electrical signals. Doctor Holt discussed his work identifying a key family of proteins that may form the channel for sound to be transduced to signal. Doctor Holt also discussed how targeting TMC1, a part of this protein family, using gene therapy restored hearing in a mouse model of TMC1 deafness. As this mutation also causes deafness in humans, gene therapy may be a potential treatment.

This seminar focused on the genes and proteins required for sensory transduction in the mammalian inner ear. The sensory cells of the inner ear, known as hair cells, convert mechanical information, such as sound, into electrical signals. The key protein at the center of the process is a mechanosensitive ion channel. The molecular identity of this ion channel has been a major focus of the ion channel field for the last several decades. Now, for the first time, a solid candidate has emerged, TMC1. TMC stands for Transmembrane Channel-like and includes a family of eight proteins, all with unknown function. TMC1 and closely related family member, TMC2, are expressed in inner ear hair cells and may form the elusive mechanosensory transduction channel.

To further characterize TMC1, to investigate structure-function relationships in TMC1 and to identify a pore region in TMC1, Doctor Holt’s lab used cysteine substitution for several key TMC1 amino acids, selected as possible pore-lining residues. Application of cysteine modification reagents altered properties of hair cell sensory transduction in real-time, including current amplitudes and calcium selectivity. The data provide compelling evidence that these residues line the permeation pathway of sensory transduction channels in inner ear hair cells.

TMC1 is also a common target of genetic mutations that cause deafness in humans and mice. To investigate the possibility of restoring auditory function in mouse models of human deafness, they used wildtype TMC1 cDNA packaged into AAV vectors. The AAV-TMC1 vectors were injected into the inner ears of deaf TMC1 mutant mice. They found that the AAV-TMC1 vectors restored auditory function at the cellular level, the systems level and the behavioral level. He concluded that TMC1 gene therapy may be a viable strategy for translation to clinical application for the benefit of patients who suffer TMC1 deafness.