Calcium and Integrin-binding protein 2 (CIB2) controls force sensitivity of the mechanotransducer channels in cochlear outer hair cells.

Calcium and Integrin-Binding Protein 2 (CIB2) is an essential subunit of the mechano-electrical transduction (MET) complex in mammalian auditory hair cells. CIB2 binds to pore-forming subunits of the MET channel, TMC1/2 and is required for their transport and/or retention at the tips of mechanosensory stereocilia. Since genetic ablation of CIB2 results in complete loss of MET currents, the exact role of CIB2 in the MET complex remains elusive. Here, we generated a new mouse strain with deafness-causing p.R186W mutation in Cib2 and recorded small but still measurable MET currents in the cochlear outer hair cells. We found that R186W variant causes increase of the resting open probability of MET channels, steeper MET current dependence on hair bundle deflection (I-X curve), loss of fast adaptation, and increased leftward shifts of I-X curves upon hair cell depolarization. Combined with AlphaFold2 prediction that R186W disrupts one of the multiple interacting sites between CIB2 and TMC1/2, our data suggest that CIB2 mechanically constraints TMC1/2 conformations to ensure proper force sensitivity and dynamic range of the MET channels. Using a custom piezo-driven stiff probe deflecting the hair bundles in less than 10 µs, we also found that R186W variant slows down the activation of MET channels. This phenomenon, however, is unlikely to be due to direct effect on MET channels, since we also observed R186W-evoked disruption of the electron-dense material at the tips of mechanotransducing stereocilia and the loss of membrane-shaping BAIAP2L2 protein from the same location. We concluded that R186W variant of CIB2 disrupts force sensitivity of the MET channels and force transmission to these channels.

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Patellofemoral pain and asymmetrical hip rotation.

BACKGROUND AND PURPOSE: Patellofemoral joint problems are the most common overuse injury of the lower extremity, and altered femoral or hip rotation may play a role in patellofemoral pain. The purpose of this case report is to describe the evaluation of and intervention for a patient with asymmetrical hip rotation and patellofemoral pain. CASE DESCRIPTION: The patient was a 15-year-old girl with an 8-month history of anterior right knee pain, without known trauma or injury. Prior to intervention, her score on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was 24%. Right hip medial (internal) rotation was less than left hip medial rotation, and manual muscle testing showed weakness of the right hip internal rotator and abductor muscles. The intervention was aimed at increasing right hip medial rotation, improving right hip muscle strength (eg, the muscle force exerted by a muscle or a group of muscles to overcome a resistance), and eliminating anterior right knee pain. OUTCOMES: After 6 visits (14 days), passive left and right hip medial rotations were symmetrical, and her right hip internal rotator and abductor muscle grades were Good plus. Her WOMAC score was 0%. DISCUSSION: The patient had right patellofemoral pain and an uncommon pattern of asymmetrical hip rotation, with diminished hip medial rotation and excessive hip lateral (external) rotation on the right side. The patient's outcomes suggest that femoral or hip joint asymmetry may be related to patellofemoral joint pain.