Academic Journal
Next generation sequencing identifies novel PMPCA variants in patients with dominant optic atrophy
| العنوان: | Next generation sequencing identifies novel PMPCA variants in patients with dominant optic atrophy |
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| المؤلفون: | Charif, Majida, Chevrollier, Arnaud, Gueguen, Naïg, Kane, Selma, Bris, Céline, Goudenège, David, Desquiret-Dumas, Valerie, Meunier, Isabelle, Mochel, Fanny, Jeanjean, Luc, Varenne, Fanny, Procaccio, Vincent, Reynier, Pascal, Bonneau, Dominique, Amati-Bonneau, Patrizia, Lenaers, Guy |
| المساهمون: | Université Mohamed 1 Oujda MAROC, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Physiologie Fonctionnelle des Organismes Marins (PFOM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff = Roscoff Marine Station (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) |
| المصدر: | ISSN: 2073-4425 ; Genes ; https://hal.science/hal-03861086 ; Genes, 2022, 13 (7), pp.1202. ⟨10.3390/genes13071202⟩. |
| بيانات النشر: | CCSD MDPI |
| سنة النشر: | 2022 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | Dominant optic atrophy, mitochondrial peptidase, mitochondrial dynamic, heterozygous variants, retinal ganglion cell degeneration, [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; 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 α 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>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients’ fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.3390/genes13071202 |
| الاتاحة: | https://hal.science/hal-03861086 https://hal.science/hal-03861086v1/document https://hal.science/hal-03861086v1/file/GENEJOURNAL-S-21-00887%20%282%29.pdf https://doi.org/10.3390/genes13071202 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.66F7C905 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/genes13071202 |
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