protocadherin15

Protocadherin-15, encoded by the PCDH15 gene, is a member of the protocadherin subfamily of the cadherin superfamily. It is a single-pass transmembrane protein with an extracellular domain containing multiple cadherin repeats and is expressed in the sensory epithelia of the inner ear and retina, among other tissues.

In the inner ear, PCDH15 participates in the formation of tip links that connect the tips of adjacent stereocilia in cochlear hair cells. Working in concert with cadherin-23, PCDH15 forms heterophilic extracellular linkages that are essential for mechanotransduction and the conversion of mechanical stimuli into electrical signals. The cytoplasmic tail of PCDH15 interacts with scaffolding proteins such as harmonin (USH1C), linking the tip link to the actin-rich cytoskeleton.

Mutations in PCDH15 cause autosomal recessive non-syndromic deafness (DFNB23) and Usher syndrome type 1F (USH1F). Usher 1F is characterized by congenital hearing loss and balance problems with progressive retinal degeneration, leading to vision loss. Depending on the mutation, individuals may present with non-syndromic deafness or Usher syndrome.

The gene produces multiple isoforms through alternative splicing and promoter usage. These isoforms differ in their extracellular and cytoplasmic regions, which may affect interactions with intracellular partners and the stability of the tip-link complex.

Research on PCDH15 includes studies in mouse and zebrafish models to understand hair-cell mechanotransduction and Usher syndrome pathogenesis. Therapeutic approaches under exploration include gene-based strategies to restore or compensate for PCDH15 function, as well as exon- or mutation-specific approaches.