Usher Proteins in the Inner Ear Structure and Function

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Usher syndrome (USH) is a devastating disease that represents a most prevalent form of inherited recessive deafness associated with blindness. In the inner ear hair cells, USH proteins constitute the components of stereocilia bundle and mechanoelectrical transduction (MET) machinery, including stereocilia tip links. We have previously identified the CIB2 gene encoding Calcium and Integrin-Binding protein 2 (CIB2) as the cause of USH1J and non-syndromic deafness (DFNB48) in diverse populations.{Patel, 2015 #561;Riazuddin, 2012 #68;Seco, 2016 #604} We have found CIB2 in the hair cell stereocilia in rodents, but its exact function was unknown. In the previous period of funding, we have generated a mouse model carrying the human deafness-related Cib2 variant (Cib2F91S knock-in) and characterized it together with a mouse line lacking CIB2 (Cib2tm1a). We found that both these mouse strains are deaf and have no conventional MET responses in the auditory hair cells, despite the presence of tip links that normally gate the MET channels and despite apparently unchanged localization of mutant CIB2 in the stereocilia of Cib2F91S/F91S mice. However, Piezo2-dependent reverse-polarity mechanosensitivity was not affected by CIB2 deficiency. We also found that CIB2 binds to the components of the hair cell MET complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 variants. We concluded that CIB2 is an essential component of the MET machinery.{Giese, 2017 #626} This novel component of the MET machinery is particularly interesting because it may be responsible for at least some of the multiple well-known effects of Ca2+ on the hair cell mechanotransduction. In this project, we will explore the exact role of CIB2 in mechanotransduction. Towards this end, we have already generated another knock-in mouse strain (Cib2R186W). R186W mutation does not affect CIB2 interaction with TMC1/2 but impairs calcium buffering ability of CIB2. This new strain will be compared to our previously generated Cib2F91S knock-in allele that impairs CIB2 interaction with TMC1/2, leading to the loss of MET. Our studies also established that CIB2 deficiency results in abnormal growth of the transducing shorter row stereocilia in the hair bundle without affecting non-transducing tallest row stereocilia.{Giese, 2017 #626} Thus, CIB2 may represent an important molecule, linking MET channel activity and stereocilia actin core remodeling. The existence of such link was established in our parallel study.{Velez-Ortega, 2017} Here, we will determine how CIB2 controls the height of the transducing stereocilia in the auditory hair cells. Finally, we have also found that CIB2 deficiency results in decreased number of the inner hair cell (IHC) synapses. Therefore, we will investigate the potential mechanisms of CIB2 involvement in the IHC synaptic function. The expected outcomes of this study are to uncover (a) the precise mechanism of deafness associated with CIB2 deficiency and (b) the physiological role of CIB2 protein in hair cell functions, especially in MET and neurotransmission. The potential for positive impact is inherent; deciphering the functions of proteins encoded by USH genes is a critical step towards the development of actual therapies for the treatment and/or prevention of this debilitating, lifelong disease
Effective start/end date12/1/1711/30/23


  • University of Maryland at Baltimore: $1,056,424.00


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