{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T01:15:08Z","timestamp":1775610908768,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an \u03b1 subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G&gt;A and c.1547G&gt;A) classified with uncertain pathological significance. Functional assays on patients\u2019 fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced \u03b1-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration.<\/jats:p>","DOI":"10.3390\/genes13071202","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T10:21:33Z","timestamp":1657016493000},"page":"1202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3301-4305","authenticated-orcid":false,"given":"Majida","family":"Charif","sequence":"first","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda 60000, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5135-6643","authenticated-orcid":false,"given":"Arnaud","family":"Chevrollier","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-8121","authenticated-orcid":false,"given":"Na\u00efg","family":"Gueguen","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Selma","family":"Kane","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Bris","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Gouden\u00e8ge","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Desquiret-Dumas","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Meunier","sequence":"additional","affiliation":[{"name":"National Reference Centre for Inherited Sensory Diseases, University Hospital of Montpellier, University of Montpellier, 34000 Montpellier, France"},{"name":"Institut des Neurosciences de Montpellier, INSERM U1051, Universit\u00e9 de Montpellier, 34000 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanny","family":"Mochel","sequence":"additional","affiliation":[{"name":"Department of Genetics, AP-HP, Piti\u00e9-Salp\u00eatri\u00e8re University Hospital, 75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Jeanjean","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, N\u00eemes University Hospital, CEDEX 9, 30900 N\u00eemes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0107-447X","authenticated-orcid":false,"given":"Fanny","family":"Varenne","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, H\u00f4pital Pierre Paul Riquet CHU Purpan, 31300 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1537-4684","authenticated-orcid":false,"given":"Vincent","family":"Procaccio","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Genetics, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-4608","authenticated-orcid":false,"given":"Pascal","family":"Reynier","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Bonneau","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Genetics, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Amati-Bonneau","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2736-3349","authenticated-orcid":false,"given":"Guy","family":"Lenaers","sequence":"additional","affiliation":[{"name":"MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"Service de Neurologie, University Hospital Angers, 49933 Angers, 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