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Article

Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy

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MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, SFR ICAT, Université d’Angers, 49933 Angers, France
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Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda 60000, Morocco
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Departments of Biochemistry and Molecular Biology, University Hospital Angers, 49933 Angers, France
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National Reference Centre for Inherited Sensory Diseases, University Hospital of Montpellier, University of Montpellier, 34000 Montpellier, France
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Institut des Neurosciences de Montpellier, INSERM U1051, Université de Montpellier, 34000 Montpellier, France
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Department of Genetics, AP-HP, Pitié-Salpêtrière University Hospital, 75013 Paris, France
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Department of Ophthalmology, Nîmes University Hospital, CEDEX 9, 30900 Nîmes, France
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Department of Ophthalmology, Hôpital Pierre Paul Riquet CHU Purpan, 31300 Toulouse, France
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Departments of Genetics, University Hospital Angers, 49933 Angers, France
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Service de Neurologie, University Hospital Angers, 49933 Angers, France
*
Author to whom correspondence should be addressed.
Academic Editors: Michele Cioffi and Maria Teresa Vietri
Genes 2022, 13(7), 1202; https://doi.org/10.3390/genes13071202
Received: 14 March 2022 / Revised: 11 April 2022 / Accepted: 1 July 2022 / Published: 5 July 2022
(This article belongs to the Collection Genotype-Phenotype Study in Disease)
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. View Full-Text
Keywords: dominant optic atrophy; mitochondrial peptidase; mitochondrial dynamic; heterozygous variants; retinal ganglion cell degeneration dominant optic atrophy; mitochondrial peptidase; mitochondrial dynamic; heterozygous variants; retinal ganglion cell degeneration
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MDPI and ACS Style

Charif, M.; Chevrollier, A.; Gueguen, N.; Kane, S.; Bris, C.; Goudenège, D.; Desquiret-Dumas, V.; Meunier, I.; Mochel, F.; Jeanjean, L.; Varenne, F.; Procaccio, V.; Reynier, P.; Bonneau, D.; Amati-Bonneau, P.; Lenaers, G. Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy. Genes 2022, 13, 1202. https://doi.org/10.3390/genes13071202

AMA Style

Charif M, Chevrollier A, Gueguen N, Kane S, Bris C, Goudenège D, Desquiret-Dumas V, Meunier I, Mochel F, Jeanjean L, Varenne F, Procaccio V, Reynier P, Bonneau D, Amati-Bonneau P, Lenaers G. Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy. Genes. 2022; 13(7):1202. https://doi.org/10.3390/genes13071202

Chicago/Turabian Style

Charif, Majida, Arnaud Chevrollier, Naïg Gueguen, Selma Kane, Céline Bris, David Goudenège, Valerie Desquiret-Dumas, Isabelle Meunier, Fanny Mochel, Luc Jeanjean, Fanny Varenne, Vincent Procaccio, Pascal Reynier, Dominique Bonneau, Patrizia Amati-Bonneau, and Guy Lenaers. 2022. "Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy" Genes 13, no. 7: 1202. https://doi.org/10.3390/genes13071202

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