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@ARTICLE{Caporali:151660,
      author       = {Caporali, Leonardo and Magri, Stefania and Legati, Andrea
                      and Del Dotto, Valentina and Tagliavini, Francesca and
                      Balistreri, Francesca and Nasca, Alessia and La Morgia,
                      Chiara and Carbonelli, Michele and Valentino, Maria L. and
                      Lamantea, Eleonora and Baratta, Silvia and Schöls, Ludger
                      and Schüle, Rebecca and Barboni, Piero and Cascavilla,
                      Maria L. and Maresca, Alessandra and Capristo,
                      Mariantonietta and Ardissone, Anna and Pareyson, Davide and
                      Cammarata, Gabriella and Melzi, Lisa and Zeviani, Massimo
                      and Peverelli, Lorenzo and Lamperti, Costanza and Marzoli,
                      Stefania B. and Fang, Mingyan and Synofzik, Matthis and
                      Ghezzi, Daniele and Carelli, Valerio and Taroni, Franco},
      title        = {{ATP}ase {D}omain {AFG}3{L}2 {M}utations {A}lter {OPA}1
                      {P}rocessing and {C}ause {O}ptic {N}europathy},
      journal      = {Annals of neurology},
      volume       = {88},
      number       = {1},
      issn         = {1531-8249},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2020-01239},
      pages        = {18 - 32},
      year         = {2020},
      abstract     = {ObjectiveDominant 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.MethodsWe 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.ResultsTwelve 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.InterpretationThis
                      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},
      keywords     = {ATP-Dependent Proteases: genetics / ATPases Associated with
                      Diverse Cellular Activities: genetics / Adolescent / Adult /
                      Aged / Child / Female / GTP Phosphohydrolases: genetics /
                      Genetic Testing / High-Throughput Nucleotide Sequencing /
                      Humans / Male / Middle Aged / Mutation / Optic Atrophy:
                      genetics / Optic Nerve Diseases: genetics / Pedigree / Exome
                      Sequencing / Young Adult},
      cin          = {AG Gasser / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000024},
      pnm          = {344 - Clinical and Health Care Research (POF3-344) / 345 -
                      Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-344 / G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7383914},
      pubmed       = {pmid:32219868},
      doi          = {10.1002/ana.25723},
      url          = {https://pub.dzne.de/record/151660},
}