Deficient forward transduction and enhanced reverse transduction in the alpha tectorin C1509G human hearing loss mutation.
Most forms of hearing loss are associated with loss of cochlear outer hair cells (OHCs). OHCs require the tectorial membrane (TM) for stereociliary bundle stimulation (forward transduction) and active feedback (reverse transduction). Alpha tectorin is a protein constituent of the TM and the C1509G mutation in alpha tectorin in humans results in autosomal dominant hearing loss. We engineered and validated this mutation in mice and found that the TM was shortened in heterozygous Tecta(C1509G/+) mice, reaching only the first row of OHCs. Thus, deficient forward transduction renders OHCs within the second and third rows non-functional, producing partial hearing loss. Surprisingly, both Tecta(C1509G/+) and Tecta(C1509G/C1509G) mice were found to have increased reverse transduction as assessed by sound- and electrically-evoked otoacoustic emissions. We show that an increase in prestin, a protein necessary for electromotility, in all three rows of OHCs underlies this phenomenon. This mouse model demonstrates a human hearing loss mutation in which OHC function is altered through a non-cell-autonomous variation in prestin.
Pubmed ID: 20142329 RIS Download
Amino Acid Substitution | Animals | Electrophysiological Phenomena | Extracellular Matrix Proteins | GPI-Linked Proteins | Gene Knock-In Techniques | Hair Cells, Auditory, Outer | Hearing Loss | Humans | Membrane Glycoproteins | Mice | Molecular Motor Proteins | Mutation | Tectorial Membrane