Journal Article

DZNE-2020-01239

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Caporali, L. ; Magri, S. ; Legati, A. ; Del Dotto, V. ; Tagliavini, F. ; Balistreri, F. ; Nasca, A. ; La Morgia, C. ; Carbonelli, M. ; Valentino, M. L. ; Lamantea, E. ; Baratta, S. ; Schöls, L.DZNE* ; Schüle, R.DZNE* ; Barboni, P. ; Cascavilla, M. L. ; Maresca, A. ; Capristo, M. ; Ardissone, A. ; Pareyson, D. ; Cammarata, G. ; Melzi, L. ; Zeviani, M. ; Peverelli, L. ; Lamperti, C. ; Marzoli, S. B. ; Fang, M. ; Synofzik, M.DZNE* ; Ghezzi, D. ; Carelli, V. ; Taroni, F.

2020
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/ana.25723

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

Keyword(s): ATP-Dependent Proteases: genetics (MeSH) ; ATPases Associated with Diverse Cellular Activities: genetics (MeSH) ; Adolescent (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Child (MeSH) ; Female (MeSH) ; GTP Phosphohydrolases: genetics (MeSH) ; Genetic Testing (MeSH) ; High-Throughput Nucleotide Sequencing (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Optic Atrophy: genetics (MeSH) ; Optic Nerve Diseases: genetics (MeSH) ; Pedigree (MeSH) ; Exome Sequencing (MeSH) ; Young Adult (MeSH)

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Functional Neurogeriatrics (AG Maetzler)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2020

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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