A conserved function of Pkhd1l1, a mammalian hair cell stereociliary coat protein, in regulating hearing in zebrafish

Pkhd1l1 is predicted to encode a very large type-I transmembrane protein, but its function has largely remained obscure. Recently, it was shown that Pkhdl1l1 is a component of the coat that decorates stereocilia of outer hair cells in the mouse ear. Consistent with this localization, conditional deletion of Pkhd1l1 specifically from hair cells, was associated with progressive hearing loss. In the zebrafish, there are two paralogous pkhd1l1 genes - pkhd1l1 alpha and pkhd1l1 beta. Using CRISPR-Cas9 mediated gene editing, we generated loss-of-function alleles for both and show that the double mutants exhibit nonsense-mediated-decay (NMD) of the RNAs. With behavioural assays, we demonstrate that zebrafish pkhd1l1 genes also regulate hearing; however, in contrast to Pkhd1l1 mutant mice, which develop progressive hearing loss, the double mutant zebrafish exhibited statistically significant hearing loss even from the larval stage. Our data highlight a conserved function of Pkhd1l1 in hearing and based on these findings from animal models, we postulate that PKHD1L1 could be a candidate gene for sensorineural hearing loss (SNHL) in humans.

Automated summary

Pkhd1l1 is a gene predicted to encode a large transmembrane protein whose function has been unclear. Recent studies have shown that Pkhdl1l1 is a membrane protein that decorates the stereocilia of outer hair cells in mice. Conditional deletion of Pkhd1l1 specifically from hair cells in mice was associated with progressive hearing loss. In zebrafish, there are two paralogous pkhd1l1 genes, and loss-of-function alleles for both genes were generated using CRISPR-Cas9 mediated gene editing, leading to NMD of the RNAs. Behavioral assays demonstrated that zebrafish pkhd1l1 genes also regulate hearing, and the double mutant zebrafish exhibited significant hearing loss even at the larval stage, unlike the Pkhd1l1 mutant mice. These findings suggest that PKHD1L1 could be a candidate gene for sensorineural hearing loss in humans.