> Detailanzeige

Caporali, Leonardo; Magri, Stefania; Legati, Andrea; Del Dotto, Valentina; Tagliavini, Francesca; Balistreri, Francesca; Nasca, Alessia; La Morgia, Chiara; Carbonelli, Michele; Valentino, Maria L.; Lamantea, Eleonora; Baratta, Silvia; Schöls, Ludger; Schüle, Rebecca; Barboni, Piero; Cascavilla, Maria L.; Maresca, Alessandra; Capristo, Mariantonietta; Ardissone, Anna; Pareyson, Davide; Cammarata, Gabriella; Melzi, Lisa; Zeviani, Massimo; Peverelli, Lorenzo; [...]

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Literatur-
verwaltung

Zur
Merkliste

Lösche von
Merkliste

Per Whatsapp teilen

Schließen

Merkliste



Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
  • Medientyp: E-Artikel
  • Titel: ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy
  • Beteiligte: Caporali, Leonardo; Magri, Stefania; Legati, Andrea; Del Dotto, Valentina; Tagliavini, Francesca; Balistreri, Francesca; Nasca, Alessia; La Morgia, Chiara; Carbonelli, Michele; Valentino, Maria L.; Lamantea, Eleonora; Baratta, Silvia; Schöls, Ludger; Schüle, Rebecca; Barboni, Piero; Cascavilla, Maria L.; Maresca, Alessandra; Capristo, Mariantonietta; Ardissone, Anna; Pareyson, Davide; Cammarata, Gabriella; Melzi, Lisa; Zeviani, Massimo; Peverelli, Lorenzo; [...]
  • Erschienen: Wiley, 2020
  • Erschienen in: Annals of Neurology
  • Sprache: Englisch
  • DOI: 10.1002/ana.25723
  • ISSN: 1531-8249; 0364-5134
  • Schlagwörter: Neurology (clinical) ; Neurology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. <jats:italic>OPA1</jats:italic> mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We screened 286 index cases presenting optic atrophy, negative for <jats:italic>OPA1</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Twelve cases (4%) were found to carry novel variants in <jats:italic>AFG3L2,</jats:italic> 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 <jats:italic>de novo</jats:italic> mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated <jats:italic>AFG3L2</jats:italic> mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated <jats:italic>AFG3L2</jats:italic> mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated <jats:italic>AFG3L2</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>This study demonstrates that mutations in <jats:italic>AFG3L2</jats:italic> are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with <jats:italic>AFG3L2</jats:italic> mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 <jats:bold>ANN NEUROL 2020;88:18–32</jats:bold></jats:p></jats:sec>