RESUMEN
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'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 transcriptional 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.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Catarata/genética , Sordera/genética , Mutación , Complejo de la Endopetidasa Proteasomal/genética , Proteolisis , Estrés Fisiológico , Proteínas de Pez Cebra/genética , Adolescente , Animales , Catarata/patología , Niño , Preescolar , Consanguinidad , Sordera/fisiopatología , Femenino , Humanos , Lactante , Masculino , Factor Nuclear 1 de Respiración/genética , Linaje , Fenotipo , Inhibidores de Proteasoma/farmacología , Proteolisis/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Síndrome , Ubiquitina/metabolismo , Pez Cebra/genéticaRESUMEN
OBJECTIVES: 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.