Title: Proteasome subunit <i>PSMC3</i> variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress
Abstract: Article5 June 2020Open Access Source DataTransparent process Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress Ariane Kröll-Hermi Ariane Kröll-Hermi Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Frédéric Ebstein Frédéric Ebstein Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Corinne Stoetzel Corinne Stoetzel Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Search for more papers by this author Véronique Geoffroy Véronique Geoffroy Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Search for more papers by this author Elise Schaefer Elise Schaefer Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Sophie Scheidecker Sophie Scheidecker Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Séverine Bär Séverine Bär Laboratoire de Génétique Moléculaire, Génomique, Microbiologie (GMGM), UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, Strasbourg, France Search for more papers by this author Masanari Takamiya Masanari Takamiya Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Koichi Kawakami Koichi Kawakami Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan Search for more papers by this author Barbara A Zieba Barbara A Zieba Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Fouzia Studer Fouzia Studer Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Valerie Pelletier Valerie Pelletier Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Carine Eyermann Carine Eyermann Service de chirurgie ORL, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Claude Speeg-Schatz Claude Speeg-Schatz Department of Ophthalmology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Vincent Laugel Vincent Laugel Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Dan Lipsker Dan Lipsker Faculté de Médecine, Hôpitaux Universitaires, Université de Strasbourg et Clinique Dermatologique, Strasbourg, France Search for more papers by this author Florian Sandron Florian Sandron orcid.org/0000-0001-7491-0283 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Steven McGinn Steven McGinn Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Anne Boland Anne Boland Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Jean-François Deleuze Jean-François Deleuze Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Centre d’études du polymorphisme humain-Fondation Jean Dausset, Paris, France Search for more papers by this author Lauriane Kuhn Lauriane Kuhn CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Johana Chicher Johana Chicher CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Philippe Hammann Philippe Hammann CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Sylvie Friant Sylvie Friant orcid.org/0000-0002-5412-6288 Laboratoire de Génétique Moléculaire, Génomique, Microbiologie (GMGM), UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, Strasbourg, France Search for more papers by this author Christelle Etard Christelle Etard Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Elke Krüger Corresponding Author Elke Krüger [email protected] orcid.org/0000-0002-2551-242X Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Jean Muller Corresponding Author Jean Muller [email protected] orcid.org/0000-0002-7682-559X Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Uwe Strähle Corresponding Author Uwe Strähle [email protected] Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Hélène Dollfus Corresponding Author Hélène Dollfus [email protected] orcid.org/0000-0002-2249-895X Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Ariane Kröll-Hermi Ariane Kröll-Hermi Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Frédéric Ebstein Frédéric Ebstein Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Corinne Stoetzel Corinne Stoetzel Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Search for more papers by this author Véronique Geoffroy Véronique Geoffroy Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Search for more papers by this author Elise Schaefer Elise Schaefer Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Sophie Scheidecker Sophie Scheidecker Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Séverine Bär Séverine Bär Laboratoire de Génétique Moléculaire, Génomique, Microbiologie (GMGM), UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, Strasbourg, France Search for more papers by this author Masanari Takamiya Masanari Takamiya Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Koichi Kawakami Koichi Kawakami Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan Search for more papers by this author Barbara A Zieba Barbara A Zieba Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Fouzia Studer Fouzia Studer Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Valerie Pelletier Valerie Pelletier Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Carine Eyermann Carine Eyermann Service de chirurgie ORL, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Claude Speeg-Schatz Claude Speeg-Schatz Department of Ophthalmology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Vincent Laugel Vincent Laugel Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Dan Lipsker Dan Lipsker Faculté de Médecine, Hôpitaux Universitaires, Université de Strasbourg et Clinique Dermatologique, Strasbourg, France Search for more papers by this author Florian Sandron Florian Sandron orcid.org/0000-0001-7491-0283 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Steven McGinn Steven McGinn Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Anne Boland Anne Boland Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Search for more papers by this author Jean-François Deleuze Jean-François Deleuze Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France Centre d’études du polymorphisme humain-Fondation Jean Dausset, Paris, France Search for more papers by this author Lauriane Kuhn Lauriane Kuhn CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Johana Chicher Johana Chicher CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Philippe Hammann Philippe Hammann CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France Search for more papers by this author Sylvie Friant Sylvie Friant orcid.org/0000-0002-5412-6288 Laboratoire de Génétique Moléculaire, Génomique, Microbiologie (GMGM), UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, Strasbourg, France Search for more papers by this author Christelle Etard Christelle Etard Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Elke Krüger Corresponding Author Elke Krüger [email protected] orcid.org/0000-0002-2551-242X Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany Search for more papers by this author Jean Muller Corresponding Author Jean Muller [email protected] orcid.org/0000-0002-7682-559X Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Uwe Strähle Corresponding Author Uwe Strähle [email protected] Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany Search for more papers by this author Hélène Dollfus Corresponding Author Hélène Dollfus [email protected] orcid.org/0000-0002-2249-895X Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Search for more papers by this author Author Information Ariane Kröll-Hermi1,2,‡, Frédéric Ebstein3,‡, Corinne Stoetzel1,‡, Véronique Geoffroy1,‡, Elise Schaefer1,4, Sophie Scheidecker1,5, Séverine Bär6, Masanari Takamiya2, Koichi Kawakami7,8, Barbara A Zieba3, Fouzia Studer9, Valerie Pelletier4,9, Carine Eyermann10, Claude Speeg-Schatz11, Vincent Laugel1,12, Dan Lipsker13, Florian Sandron14, Steven McGinn14, Anne Boland14, Jean-François Deleuze14,15, Lauriane Kuhn16, Johana Chicher16, Philippe Hammann16, Sylvie Friant6, Christelle Etard2, Elke Krüger *,3, Jean Muller *,1,5, Uwe Strähle *,2 and Hélène Dollfus *,1,4,9 1Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France 2Karlsruhe Institute of Technology (KIT), Institut für Biologische und Chemische Systeme (IBCS, BIP), Eggenstein-Leopoldshafen, Germany 3Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Greifswald, Germany 4Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 5Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 6Laboratoire de Génétique Moléculaire, Génomique, Microbiologie (GMGM), UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, Strasbourg, France 7Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan 8Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan 9Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 10Service de chirurgie ORL, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 11Department of Ophthalmology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 12Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 13Faculté de Médecine, Hôpitaux Universitaires, Université de Strasbourg et Clinique Dermatologique, Strasbourg, France 14Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France 15Centre d’études du polymorphisme humain-Fondation Jean Dausset, Paris, France 16CNRS FRC1589, Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, Strasbourg, France ‡These authors contributed equally to this work *Corresponding author. Tel: +49 3834 865400; E-mail: [email protected] *Corresponding author. Tel: +33 369550777; E-mail: [email protected] *Corresponding author. Tel: +49 72160828327; E-mail: [email protected] *Corresponding author. Tel: +33 368853341; E-mail: [email protected] EMBO Mol Med (2020)12:e11861https://doi.org/10.15252/emmm.201911861 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract 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. Synopsis Whole genome sequencing in a large consanguineous family with neurosensory syndrome revealed a unique homozygous deep intronic pathogenic variant in PSMC3, encoding one of the proteasome subunit. Further in vitro and in vivo analyses confirmed the pathogenicity of the PSMC3 mutation. This is the first implication of a 26S proteasome AAA-ATPase of the 19S proteasome regulatory complex in a neurosensorial disease with early onset cataract and deafness. Functional analysis using patient's cells revealed a pathogenic mechanism with proteasome impairment resulting in proteotoxic stress with over-activation of the TCF11/Nrf1 transcriptional pathway. Zebrafish model reproduces the human phenotype with cataract and ear malformations. PSMC3 plays a major role in inner ear, lens and central nervous system development. These results expand our knowledge on the genetic background of the emerging proteasomopathy. The paper explained Problem Early-onset deafness is one of the most common causes of developmental disorder in children (prevalence of 2–4/1,000 infants), and similarly, early-onset cataract is the most important cause of paediatric visual impairment worldwide (prevalence 2–13.6/10,000) accounting for 10% of the causes of childhood blindness. Many genes have already been implicated for each of these conditions independently but only very few genes identified when cataract and early-onset deafness occur together. Indeed, patients with both conditions are very rare and often linked to teratogenic exposure during pregnancy. In this study, we therefore aim at identifying the molecular cause of cases with syndromic early-onset deafness and congenital cataracts. Results Using whole-genome sequencing combined with homozygosity mapping and bioinformatics prioritization, we uncovered a homozygous deep intronic variation in the PSMC3 gene in three affected patients from a very large consanguineous family presenting with early-onset cataract and deafness. PSMC3 encodes one of the proteasome subunits and more specifically Rpt5, the 26S proteasome AAA-ATPase subunit of the 19S proteasome complex responsible for recognition, unfolding and translocation of substrates into the 20S proteolytic cavity of the proteasome. The ubiquitin–proteasome system (UPS) is a major cellular system that degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling including development. Using multiple approaches including proteomics, cellular biology (on patient's cells) and animal modelling (zebrafish), we could confirm the impact of this variation (transcription of a cryptic exon introducing a stop codon) on proteasome function and linked this to the patients’ phenotype. Impact This is the first implication of the 26S proteasome AAA-ATPase subunit in a disease with the description of biallelic pathogenic variations in the context of the emerging proteasomopathies that include PSMA3, PSMB1, PSMB4, PSMB8, PSMB9, PSMD12, PSMG2 and POMP genes that are linked to loss-of-function variations. These results open new insights into the role of the proteasome or at least PSMC3 in inner ear, lens and central nervous system development. Identifying novel genes implicated in such rare diseases will improve the genetic counselling and give affected families the opportunity to have access to preimplantation genetic diagnosis and prenatal testing. Introduction Early-onset deafness is one of the most common causes of developmental disorder in children (prevalence rate of 2–4/1,000 infants), and identically, early-onset cataract is the most important cause of paediatric visual impairment worldwide (prevalence form 2–13.6/10,000 according to regions) accounting for 10% of the causes of childhood blindness. Each condition can be attributed to environmental causes (intrauterine infections, inflammation, trauma or metabolic diseases) or to genetic causes with a well-recognized very high level of genetic heterogeneity with 59 known genes causing early-onset cataracts and 196 genes known to cause severe deafness (Azaiez et al, 2018; Reis & Semina, 2018). Patients presenting both entities simultaneously, early-onset severe deafness and congenital cataracts, are thought to be mainly due to teratogenic exposure during pregnancy especially infections and are, nowadays, considered to be very rare. Indeed, only very few genetic inherited entities associating both congenital cataracts and deafness have been reported so far. The Aymé-Gripp syndrome (cataract, deafness, intellectual disability, seizures and Down syndrome like facies) has been recently linked to de novo pathogenic variants in the MAF gene, a leucine zipper-containing transcription factor of the AP1 superfamily (Niceta et al, 2015). In addition, dominant pathogenic variants in WFS1 (recessive loss-of-function variants are responsible for Wolfram syndrome) have been described in children with congenital cataracts and congenital deafness presenting in the context of neonatal/infancy-onset diabetes (De Franco et al, 2017). Herein, using whole-genome sequencing, we describe a novel homozygous non-coding pathogenic variant in PSMC3 associated with severe congenital deafness and early-onset cataracts and various neurological features in three patients from a very large consanguineous family. PSMC3 encodes the 26S regulatory subunit 6A also known as the 26S proteasome AAA-ATPase subunit (Rpt5) of the 19S proteasome complex responsible for recognition, unfolding and translocation of substrates into the 20S proteolytic cavity of the proteasome (Tanaka, 2009). The proteasome is a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins to maintain cellular protein homeostasis and to control the abundance of many regulatory molecules. The 26S proteasome consists of two complexes: a catalytic 28-subunit barrel shaped core particle (20S) that is capped at the top or the bottom by one 19 subunit regulatory particle (19S). The core particle contains the catalytic subunits β1, β2 and β5 exhibiting caspase-, trypsin- and chymotrypsin-like activities, respectively. Recognition of a substrate with the requisite number and configuration of ubiquitin is mediated principally by both Rpn10 and Rpn13 subunits, which act as ubiquitin receptors (Deveraux et al, 1994; Husnjak et al, 2008). To allow substrate degradation, ubiquitin is first removed by Rpn11, a metalloprotease subunit in the lid (Yao & Cohen, 2002). The globular domains of a substrate are then unfolded mechanically by a ring-like heterohexameric complex consisting of six distinct subunits, Rpt1 to Rpt6, which belong to the ATPases associated with diverse cellular activities (AAA) family (Chen et al, 2016). PSMC3 encodes for Rpt5 involved in the substrate unfolding and translocation, which are then presumably catalysed (Lam et al, 2002; Tanaka, 2009). In mammalian cells, a major compensation mechanism for proteasome dysfunction is governed by the ER membrane-resident TCF11/Nrf1 protein (Radhakrishnan et al, 2010; Steffen et al, 2010; Sotzny et al, 2016). Typical stimuli for TCF11/Nrf1 activation include proteasome inhibition and/or impairment, which results in the release of C-terminal processed TCF11/Nrf1 fragment from the ER membrane following a complex series of molecular events involving the enzymes NGLY1 and DDI2. The cleaved TCF11/Nrf1 fragment enters then into the nucleus and acts as a transcription factor to promote the expression of ARE-responsive genes including 19S and 20S proteasome subunits, thereby augmenting the pool of proteasomes so that protein homeostasis can be preserved (Radhakrishnan et al, 2010; Steffen et al, 2010; Sotzny et al, 2016). We suggest that biallelic loss of PSMC3 causes a novel autosomal recessive syndrome with varying degrees of neurosensorial dysfunctions including the combination of cataract and deafness. Functional analysis of patient's cells revealed that although normal amount of proteasome proteins can be observed in steady-state conditions, the cells are unable to adapt to proteotoxic stress. The use of zebrafish morpholinos and CRIPSR-Cas9 assays confirmed the same combination of sensory phenotypes upon inactivating PSMC3 expression. Results Patient phenotypes Three patients with a novel syndromic neurosensory-cutaneous presentation consulted independently to our clinical centre over a period of 15 years. Careful analysis revealed that they originated from the same small village (Amarat) in the Kayseri region of Turkey and belong to the same large extended consanguineous family (Fig 1A). The proband is a male individual (II.4) diagnosed at the age of 8 months with profound perceptive deafness and subsequently benefited from a cochlear implantation. He was referred at the age of 2 years old to our centre because of visual impairment due to bilateral cataracts for which he underwent bilateral lensectomies. With years, he developed severe developmental delay and severe intellectual deficiency (no words, limited comprehension). Several facial features were noted (Table 1 and Fig 1B). In addition, severe autistic features were revealed at the age of 2.5 years old (Table 1). A full metabolic exploration was normal. At the age of 5, he developed subcutaneous deposits at the level of the knees and elbows (Fig 1C). At the age of 10, he developed white hair at the level of the two legs as opposed to the dark pigmented hair on the rest of the body. More recent examination revealed also a peripheral polyneuropathy of lower limbs. The two other patients (II.2 and II.7) were referred at the age of 1 year old and share the same severe perceptive deafness (for which they also benefited from a cochlear implantation), visual impairment due to bilateral obstruent cataracts (for which they also had bilateral lensectomies) and subcutaneous deposits. Patient II.2 did not present with autistic features but had moderate developmental delay (able to read and write few words, but no understanding of complex sentences) and