CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

Defects of CIB2, calcium‐ and integrin‐binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type‐IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2 −/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2 −/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair‐cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2 −/− mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits. Synopsis A lack of any of the first five USH1 proteins in mice leads to structural hair bundle defects in the embryo, causing congenital profound deafness, and balance dysfunction. The lack of CIB2 both in mice and humans, however, reveals that CIB2 is critical for hearing but not for balance and vision. In addition to its key role in auditory mechanoelectrical transduction, CIB2 is required for postnatal maintenance of the structural integrity of the hair bundle and hair cell survival in the cochlea. A lack of CIB2 leads to the mislocalisation of integrins in stereocilia, revealing the importance of CIB2‐mediated interactions with the extracellular matrix for the correct shaping of the auditory hair bundles. A functional CIB2 is required for normal hearing, but not for balance and vision, in both mice and humans, as we found two novel nonsense mutations leading to nonsyndromic hearing loss without signs of retinitis pigmentosa or vestibular dysfunction. Graphical Abstract A lack of any of the first five USH1 proteins in mice leads to structural hair bundle defects in the embryo, causing congenital profound deafness, and balance dysfunction. The lack of CIB2 both in mice and humans, however, reveals that CIB2 is critical for hearing but not for balance and vision.