ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Leonardo Caporali, Stefania Magri, Andrea Legati, Valentina Del Dotto, Francesca Tagliavini, Francesca Balistreri, Alessia Nasca, Chiara La Morgia, Michele Carbonelli, Maria L. Valentino, Eleonora Lamantea, Silvia Baratta, Ludger Schöls, Rebecca Schüle, Piero Barboni, Maria L. Cascavilla, Alessandra Maresca, Mariantonietta Capristo, Anna Ardissone, Davide PareysonGabriella Cammarata, Lisa Melzi, Massimo Zeviani, Lorenzo Peverelli, Costanza Lamperti, Stefania B. Marzoli, Mingyan Fang, Matthis Synofzik, Daniele Ghezzi, Valerio Carelli, Franco Taroni

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)18-32
Number of pages15
JournalAnnals of Neurology
Issue number1
Publication statusPublished - Jul 1 2020

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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