TMC function in hair cell transduction

•Over 30 TMC1 mutations have been identified that cause deafness in mice and humans.•Eight mammalian TMC genes have been identified and a few are found in invertebrates.•Hair cells express Tmc1 and Tmc2 and the proteins can be found at stereocilia tips.•Hair cells that express TMC1 or TMC2 have distinct biophysical properties.•Hair cells that express mutant TMC1 have reduced calcium selectivity.

Transmembrane channel-like (TMC) proteins 1 and 2 are necessary for hair cell mechanotransduction but their precise function is controversial. A growing body of evidence supports a direct role for TMC1 and TMC2 as components of the transduction complex. However, a number of important questions remain and alternate hypotheses have been proposed. Here we present an historical overview of the identification and cloning of Tmc genes, a discussion of mutations in TMC1 that cause deafness in mice and humans and a brief review of other members of the Tmc gene superfamily. We also examine expression of Tmc mRNAs and localization of the protein products. The review focuses on potential functions of TMC proteins and the evidence from Beethoven mice that suggests a direct role for TMC1 in hair cell mechanotransduction. Data that support alternate interpretations are also considered. The article concludes with a discussion of outstanding questions and future directions for TMC research.This article is part of a Special Issue entitled .