A scientific team in France reports that the absence of a specific protein in the inner ear or impairment of the gene that codes for it leads to profound deafness in mice and humans. The researchers believe that it is possible to consider developing gene therapy strategies for deafness caused by defects in this gene.
“The goal of our study was to identify which isoform of protocadherin-15 forms the tip-links, the essential connections of the auditory mechanotransduction machinery within mature hair cells that are needed to convert sound into electrical signals,” remarks Christine Petit, Ph.D., the lead author of the study and professor at the Institut Pasteur in Paris and at Collège de France.
Three types of protocadherin-15 are known to exist in auditory sensory cells of the inner ear but it was not clear which of these protein isoforms was essential for hearing. “Our work pinpoints the CD2 isoform of protocadherin-15 as an essential component of the tip-link and reveals that the absence of protocadherin-15 CD2 in mouse hair cells results in profound deafness,” she said.
Dr. Petit and her colleagues reported the details of their study (“The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells”) in EMBO Molecular Medicine.
Within the hair bundle—the sensory antenna of auditory sensory cells—the tip-link is a bridge-like structure that when stretched can activate the ion channel responsible for generating electrical signals from sound. Tension in the tip-link created by sound stimulation opens this channel of unknown molecular composition thus generating electrical signals and, ultimately, the perception of sound.
The researchers engineered mice that lack only the CD2 isoform of protocadherin-15 exclusively during adulthood. While the absence of this isoform led to deafness, the lack of the other protocadherin-15 isoforms in mice did not affect their hearing.
“By immunolabeling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15ex38-fl/ex38-fl Myo15-cre+/−) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells,” wrote the investigators. “The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2 in profoundly deaf children from two unrelated families extends this conclusion to humans.”
The scientists point out that these results provide critical information for the “identification of new components of the mature auditory mechano-electrical transduction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.”