Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Majida Charif; Arnaud Chevrollier; Naïg Gueguen; Céline Bris; David Goudenège; Valérie Desquiret-Dumas; Stéphanie Leruez; Estelle Colin; Audrey Meunier; Catherine Vignal; Vasily Smirnov; Sabine Defoort-Dhellemmes; Isabelle Drumare Bouvet; Cyril Goizet; Marcela Votruba; Neringa Jurkute; Patrick Yu-Wai-Man; Francesca Tagliavini; Leonardo Caporali; Chiara La Morgia; Valerio Carelli; Vincent Procaccio; Xavier Zanlonghi; Isabelle Meunier; Pascal Reynier; Dominique Bonneau; Patrizia Amati-Bonneau; Guy Lenaers

doi:10.1212/NXG.0000000000000428

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Neurol Genet. 2020 May 20;6(3):e428. doi: 10.1212/NXG.0000000000000428. eCollection 2020 Jun.

Authors

Majida Charif¹, Arnaud Chevrollier¹, Naïg Gueguen¹, Céline Bris¹, David Goudenège¹, Valérie Desquiret-Dumas¹, Stéphanie Leruez¹, Estelle Colin¹, Audrey Meunier¹, Catherine Vignal¹, Vasily Smirnov¹, Sabine Defoort-Dhellemmes¹, Isabelle Drumare Bouvet¹, Cyril Goizet¹, Marcela Votruba¹, Neringa Jurkute¹, Patrick Yu-Wai-Man¹, Francesca Tagliavini¹, Leonardo Caporali¹, Chiara La Morgia¹, Valerio Carelli¹, Vincent Procaccio¹, Xavier Zanlonghi¹, Isabelle Meunier¹, Pascal Reynier¹, Dominique Bonneau¹, Patrizia Amati-Bonneau¹, Guy Lenaers¹

Affiliation

¹ MitoLab Team (M.C., A.C., C.B., D.G., V.D.-D., S.L., V.P., P.R., D.B., P.A.-B., G.L.), UMR CNRS 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital; Genetics and immuno-cell therapy Team (M.C.), Mohammed First University, Oujda, Morocco; Departments of Biochemistry and Genetics (C.B., D.G., V.D.-D., E.C., V.P., P.R., D.B., P.A.-B.), University Hospital Angers; Department of Ophthalmology (A.M.), Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; Neuroophthalmology Department (C.V.), Rothschild Ophthalmologic Foundation, Paris; Exploration of Visual Function and Neuro-Ophthalmology Department (V.S., S.D.-D., I.D.B.), Lille University Hospital, Rue Emilie Laine, Lille Cedex; CHU Bordeaux (C.G.), Service de Génétique Médicale, Centre de Référence « Neurogénétique » and Université de Bordeaux, INSERM U 1211, Laboratoire Maladies Rares, Génétique et Métabolisme (MRGM) Bordeaux; School of Optometry and Vision Sciences (M.V.), Cardiff University and Cardiff Eye Unit, University Hospital of Wales; NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology (N.J., P.Y.-W.-M.), London; Department of Clinical Neurosciences (P.Y.-W.-M.), Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge; Cambridge Eye Unit (P.Y.-W.-M.), Addenbrooke's Hospital, Cambridge University Hospitals, UK; IRCCS Istituto Delle Scienze Neurologiche di Bologna (F.T., L.C., C.L.M., V.C.), Bellaria Hospital; Unit of Neurology (C.L.M., V.C.), Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Italy; Centre de Compétence Maladies Rares (X.Z.), Clinique Pluridisciplinaire Jules Verne, Nantes; and National Centre in Rare Diseases (I.M.), Genetics of Sensory Diseases, University Hospital, Montpellier, France.

Abstract

Objective: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Methods: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

Results: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Conclusions: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Abstract

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