Proteasome subunit variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

The ubiquitin–proteasome system degrades ubiquitin‐modified proteins to maintain protein homeostasis and to control signalling. Whole‐genome sequencing of patients with severe deafness and early‐onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient\u27s fibroblasts was however unaffected. Nevertheless, patient\u27s cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient\u27s fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient\u27s cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development

La fenêtre ronde dans la chirurgie de l'implant cochléaire : évaluation de sa visibilité par la tympanotomie postérieure par l'analyse du scanner pré-opératoire

Médecine (oto‐rhino‐laryngologie et chirurgie cervico‐faciale)Résumé : lors de la chirurgie de l'implant cochléaire, dans certains cas, la visibilité de la fenêtre ronde (FR) par la tympanotomie postérieure n’est pas suffisante, nécessitant le recours à une cochléostomie ou une voie alternative. Pour prédire la visibilité de la FR, nous avons mis au point un protocole de lecture du scanner préopératoire, testé de façon rétrospective sur 55 dossiers de patients implantés au C.H.U. de Strasbourg entre mars 2016 et mars 2018. Une corrélation statistiquement significative entre les prédictions préopératoires et les constatations peropératoires a été mise en évidence pour la visibilité de la FR et la possibilité d’y insérer le porte-électrodes. La VPP de notre protocole dépassait les 90% (97% en excluant les cas d’otospongiose et d’inflammation dans la caisse) constituant un moyen fiable et rapide pour le chirurgien de s’assurer, en préopératoire, de la faisabilité du passage par la FR ou, a contrario, de l’amener à anticiper une alternative.Summary : During cochlear implant surgery, sometimes, round window (RW) visibility through the posterior tympanotomy is not sufficient, requiring a cochleostomy or an alternative technique. To predict the visibility of the RW, we developed a preoperative CT scan protocol, which was retrospectively tested on 55 patients implanted between March 2016 and March 2018 in Strasbourg. A significant correlation was found between preoperative predictions and intraoperative findings for the visibility of the RW niche and the possibility of inserting the electrode-array through the RW. The positive predictive value of our protocol exceeded 90% (97% excluding cases with otosclerosis or inflammation) providing a reliable and fast way for the surgeon to ensure, preoperatively, the feasibility of passing through the RW or, conversely, to lead him to anticipate an alternative

La fenêtre ronde dans la chirurgie de l'implant cochléaire : évaluation de sa visibilité par la tympanotomie postérieure par l'analyse du scanner pré-opératoire

Médecine. Oto‐Rhino‐Laryngologie. Chirurgie Cervico‐FacialeRésumé : lors de la chirurgie de l'implant cochléaire, dans certains cas, la visibilité de la fenêtre ronde (FR) par la tympanotomie postérieure n’est pas suffisante, nécessitant le recours à une cochléostomie ou une voie alternative. Pour prédire la visibilité de la FR, nous avons mis au point un protocole de lecture du scanner préopératoire, testé de façon rétrospective sur 55 dossiers de patients implantés au C.H.U. de Strasbourg entre mars 2016 et mars 2018. Une corrélation statistiquement significative entre les prédictions préopératoires et les constatations peropératoires a été mise en évidence pour la visibilité de la FR et la possibilité d’y insérer le porte-électrodes. La VPP de notre protocole dépassait les 90% (97% en excluant les cas d’otospongiose et d’inflammation dans la caisse) constituant un moyen fiable et rapide pour le chirurgien de s’assurer, en préopératoire, de la faisabilité du passage par la FR ou, a contrario, de l’amener à anticiper une alternative.Summary : During cochlear implant surgery, sometimes, round window (RW) visibility through the posterior tympanotomy is not sufficient, requiring a cochleostomy or an alternative technique. To predict the visibility of the RW, we developed a preoperative CT scan protocol, which was retrospectively tested on 55 patients implanted between March 2016 and March 2018 in Strasbourg. A significant correlation was found between preoperative predictions and intraoperative findings for the visibility of the RW niche and the possibility of inserting the electrode-array through the RW. The positive predictive value of our protocol exceeded 90% (97% excluding cases with otosclerosis or inflammation) providing a reliable and fast way for the surgeon to ensure, preoperatively, the feasibility of passing through the RW or, conversely, to lead him to anticipate an alternative

Malformations of the lateral semicircular canal correlated with data from the audiogram

Number: 4 PMID: 30725208OBJECTIVES: Lateral semicircular canal (LSCC) malformations  are one of the most common inner ear malformations. The purpose of this study is to analyze the prevalence and type of hearing losses associated with LSCC malformations, compared to a control group. MATERIALS AND METHODS: We retrospectively included 109 patients (166 ears) presenting with a CT-confirmed LSCC malformation, compared to a control group (24 patients). The bony island surface and the width of the inner portion of the LSCC were measured to confirm the malformation. There results were correlated to audiogram data: sensorineural (SHNL), mixed (MHL) or conductive hearing loss (CHL) by an otologist. RESULTS: In the LSCC group, 60.9% of patients presented with an audiogram-confirmed hearing loss, especially SNHL (39.2%, n = 65) and MHL (12.7%, n = 21). Hearing was normal in 39.2% (n = 65) of the cases. Bilateral LSCC malformations (n = 57) were frequently associated with hearing loss (80.7%), SNHL in most of the cases (33.3%). Unilateral LSCC malformations were associated with hearing alterations (51.9%, n = 27), but we also observed a high rate (81%, n = 42) of contralateral abnormalities of the audiogram. CONCLUSION: LSCC malformations are commonly associated with hearing loss (61%), especially SHNL (39%). The high rate (81%) of contralateral hearing disturbances in unilateral LSCC malformations should be taken into account in the patient's daily life to avoid triggering or exacerbating any hearing loss. Otologists and radiologists must cooperate to ensure that all malformations are correctly described on CT, especially to improve the patient's education regarding hearing preservation

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

International audienceThe ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cuta-neous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The protea-some content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 tran-scriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts , suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development