Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.

Agostina Pietrantoni, Cyril Mignot, Boris Keren, Stéphane Auvin, Chiara Leoni, Giuseppe Zampino, Roberta Onesimo, Giovanna Carpentieri, Serena Cecchetti, Marco Tartaglia, Marco Ferilli, Elena Messina, Bianca E Russell, Ahna Neustad, Nicola Brunetti Pierri, Julie S Cohen, Alexis Heidlebaugh, Clay Smith, Gianfranco Bocchinfuso, Gerarda Cappuccio, Christian T Thiel, Francesca Clementina Radio, Charles Marques Lourenco, Elisabetta Flex, Paolo Calligari, Philippe M Campeau, Simone Martinelli, Cristina Calderan, Lorenzo Stella, Andrea Ciolfi, Ulrike Hüffmeier, André Reis, Yline Capri, Leonardo Salviati, Viviana Caputo

Journal: HGG advances 2024;5(4):100349

PMID: 39210597

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Abstract

The vacuolar H-ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome. Here, we report on an individual with features fitting DOORS syndrome caused by dysregulated ATP6V1C1 function, expand the clinical features associated with ATP6V1B2 pathogenic variants, and provide evidence that these ATP6V1C1/ATP6V1B2 amino acid substitutions result in a gain-of-function mechanism upregulating V-ATPase function that drives increased lysosomal acidification. We demonstrate a disruptive effect of these ATP6V1B2/ATP6V1C1 variants on lysosomal morphology, localization, and function, resulting in a defective autophagic flux and accumulation of lysosomal substrates. We also show that the upregulated V-ATPase function affects cilium biogenesis, further documenting pleiotropy. This work identifies ATP6V1C1 as a new gene associated with a neurodevelopmental phenotype resembling DOORS syndrome, documents the occurrence of a phenotypic continuum between ZLS, and DDOD and DOORS syndromes, and classify these conditions as lysosomal disorders.

Address: Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.; Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.; Department of Chemical Science and Technologies, University of Rome Tor Vergata, 00133 Rome, Italy.; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome 00168, Italy.; Electron Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.; Department of Women and Children's Health, University of Padua, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padua, Italy.; Department of Translational Medicine, "Federico II" University, 80131 Naples, Italy.; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.; Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy.; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.; Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hopitaux de Paris, Sorbonne University, Paris, France.; Service de Neurologie Pediatrique, Hopital Universitaire Robert Debré, Université Paris Cité, 75935 Paris, France.; Department of Genetics, Robert-Debré University Hospital, Assistance Publique-Hopitaux de Paris, 75935 Paris, France.; Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto 14096-160, São Paulo, Brazil.; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Translational Medicine, "Federico II" University, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Scuola Superiore Meridionale, Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy.; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, 91054 Erlangen, Germany.; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome 00168, Italy; Facoltà di Medicina e Chirurgia, Università Cattolica del S. Cuore, 00168 Rome, Italy.; Department of Pediatrics, Université de Montréal, Montréal, QC, Canada.; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: [email protected].; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy. Electronic address: [email protected].

DOI: 10.1016/j.xhgg.2024.100349

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MeSH Terms: Humans, Vacuolar Proton-Translocating ATPases, Lysosomes, Phenotype, Autophagosomes, Male, Intellectual Disability, Female, Deafness