ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Ann Neurol. 2020 Jul;88(1):18-32. doi: 10.1002/ana.25723.

Leonardo Caporali ¹, Stefania Magri ², Andrea Legati ², Valentina Del Dotto ³, Francesca Tagliavini ¹, Francesca Balistreri ², Alessia Nasca ², Chiara La Morgia ¹ ³, Michele Carbonelli ¹, Maria L Valentino ¹ ³, Eleonora Lamantea ², Silvia Baratta ², Ludger Schöls ⁴ ⁵, Rebecca Schüle ⁴ ⁵, Piero Barboni ⁶ ⁷, Maria L Cascavilla ⁷, Alessandra Maresca ¹, Mariantonietta Capristo ¹, Anna Ardissone ⁸, Davide Pareyson ⁹, Gabriella Cammarata ¹⁰, Lisa Melzi ¹⁰, Massimo Zeviani ¹¹, Lorenzo Peverelli ¹², Costanza Lamperti ², Stefania B Marzoli ¹⁰, Mingyan Fang ¹³, Matthis Synofzik ⁴ ⁵, Daniele Ghezzi ² ¹⁴, Valerio Carelli ¹ ³, Franco Taroni ²

Affiliations

1 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.
2 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
3 Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
4 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
5 German Center for Neurodegenerative Diseases, Tübingen, Germany.
6 Studio Oculistico D'Azeglio, Bologna, Italy.
7 IRCCS Ospedale San Raffaele, Milan, Italy.
8 Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
9 Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
10 Neuro-Ophthalmology Center and Ocular Electrophysiology Laboratory, IRCCS Istituto Auxologico Italiano, Capitanio Hospital, Milan, Italy.
11 Department of Neuroscience, University of Padua, Padua, Italy.
12 Neurology Unit, Azienda Socio Sanitaria Territoriale Lodi, Ospedale Maggiore di Lodi, Lodi, Italy.
13 Beijing Genomics Institute-Shenzhen, Shenzhen, China.
14 Department of Medical-Surgical Physiopathology and Transplantation, University of Milan, Milan, Italy.

PMID: 32219868 DOI: 10.1002/ana.25723

Abstract

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.

Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation Sequencing or whole exome Sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts.

Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the Others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells.

Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.

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