Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice

Abstract

Usher syndrome type 2 (USH2) is the predominant form of USH, a leading genetic cause of combined deafness and blindness. PDZD7, a paralog of two USH causative genes, USH1C and USH2D (WHRN), was recently reported to be implicated in USH2 and non-syndromic deafness. It encodes a protein with multiple PDZ domains. To understand the biological function of PDZD7 and the pathogenic mechanism caused by PDZD7 mutations, we generated and thoroughly characterized a Pdzd7 knockout mouse model. The Pdzd7 knockout mice exhibit congenital profound deafness, as assessed by auditory brainstem response, distortion product otoacoustic emission and cochlear microphonics tests, and normal vestibular function, as assessed by their behaviors. Lack of PDZD7 leads to the disorganization of stereocilia bundles and a reduction in mechanotransduction currents and sensitivity in cochlear outer hair cells. At the molecular level, PDZD7 determines the localization of the USH2 protein complex, composed of USH2A, GPR98 and WHRN, to ankle links in developing cochlear hair cells, likely through its direct interactions with these three proteins. The localization of PDZD7 to the ankle links of cochlear hair bundles also relies on USH2 proteins. In photoreceptors of Pdzd7 knockout mice, the three USH2 proteins largely remain unchanged at the periciliary membrane complex. The electroretinogram responses of both rod and cone photoreceptors are normal in knockout mice at 1 month of age. Therefore, although the organization of the USH2 complex appears different in photoreceptors, it is clear that PDZD7 plays an essential role in organizing the USH2 complex at ankle links in developing cochlear hair cells. GenBank accession numbers: KF041446, KF041447, KF041448, KF041449, KF041450, KF041451.

Whirlin and PDZ Domain-containing 7 (PDZD7) Proteins Are Both Required to Form the Quaternary Protein Complex Associated with Usher Syndrome Type 2

“…Whrn, or Pdzd7 gene causes disorganization and gradual degeneration of hair bundles in mice (10,11,16,21,22), which leads to reduction of mechanotransduction responses and hearing loss (10,11,16). Disruption of Whrn or Ush2a expression in the retina results in slow degeneration (21,22); vesicles and vacuoles were found to accumulate around the periciliary membrane complex in Whrn mutant photoreceptors (22).…”

“…USH2A and GPR98 proteins each have a very short cytoplasmic region carrying a PDZ domain-binding motif (PBM) at their C termini. Biochemical studies demonstrate that the PDZ domains of WHRN and PDZD7 are able to bind the PBMs of USH2A and GPR98 (1, 13, 16,22,25). In photoreceptors, USH2A, GPR98, and WHRN proteins show mutual dependence for normal localizations at the periciliary membrane complex, and WHRN is able to recruit USH2A and GPR98 to the periciliary membrane complex (22,26).…”

Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

“…The PDZD7 protein localization at the connecting cilium region has been shown to play a role in inner ear hair cell development (Ebermann et al, 2010). In mice, the abnormal expression of the Pdzd7 gene causes disorganization of hair bundles and may affect the establishment of mechanotransduction responses, which likely results in hearing loss (Zou et al, 2014). PDZD7 is a three‐PDZ domain protein with a central proline‐rich region.…”

“…In addition, PDZD7 is a member of the Usher quaternary protein complex (PDZD7, USH2A, GPR98 and WHRN), and localization in the ankle‐link makes it a good candidate for Usher syndrome type 2 (USH2) (Chen, Zou, Shen, Zhang, & Yang, 2014; Zou et al, 2014). USH2 is the most common Usher syndrome type.…”

“…The hair cells of Pdzd7 −/− mice display bundle morphological defects and abnormal mechanotransduction (MET) processes in OHCs while vestibular hair cells have normal MET responses. Furthermore, in reported Pdzd7 mutant mice, PDZD7 plays a limited role in localizing USH2 proteins in photoreceptors (Zou et al, 2014). Overall, our data support the contribution of PDZD7 biallelic mutations to the etiology of ARNSHL in humans.…”