1. ATPase Domain <scp> AFG3L2 </scp> Mutations Alter <scp>OPA1</scp> Processing and Cause Optic Neuropathy
- Author
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Maria Lucia Valentino, Stefania Magri, Matthis Synofzik, Lorenzo Peverelli, Mingyan Fang, Alessia Nasca, Piero Barboni, Andrea Legati, Anna Ardissone, Stefania Bianchi Marzoli, Francesca Tagliavini, Eleonora Lamantea, Silvia Baratta, Daniele Ghezzi, Costanza Lamperti, Valerio Carelli, Chiara La Morgia, Rebecca Schüle, Mariantonietta Capristo, Gabriella Cammarata, Leonardo Caporali, Francesca Balistreri, Valentina Del Dotto, Davide Pareyson, Massimo Zeviani, L Melzi, Ludger Schöls, Michele Carbonelli, Franco Taroni, Maria Lucia Cascavilla, Alessandra Maresca, 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., Schols L., Schule R., 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., Ghezzi D., Carelli V., and Taroni F.
- Subjects
Male ,0301 basic medicine ,DOA ,Gene mutation ,medicine.disease_cause ,ATP-Dependent Proteases ,ATPases Associated with Diverse Cellular Activities ,Adolescent ,Adult ,Aged ,Child ,Female ,GTP Phosphohydrolases ,Genetic Testing ,High-Throughput Nucleotide Sequencing ,Humans ,Middle Aged ,Mutation ,Optic Atrophy ,Optic Nerve Diseases ,Pedigree ,Whole Exome Sequencing ,Young Adult ,OPA1 ,genetics [Optic Atrophy] ,Optic neuropathy ,0302 clinical medicine ,genetics [ATPases Associated with Diverse Cellular Activities] ,Research Articles ,Exome sequencing ,Genetics ,genetics [Optic Nerve Diseases] ,Neurology ,Spinocerebellar ataxia ,medicine.symptom ,Research Article ,genetics [GTP Phosphohydrolases] ,Spastic gait ,Ataxia ,Biology ,SCA28 ,03 medical and health sciences ,Atrophy ,Exome Sequencing ,medicine ,ddc:610 ,AFG3L2 ,medicine.disease ,eye diseases ,optic neuropathy ,030104 developmental biology ,genetics [ATP-Dependent Proteases] ,Neurology (clinical) ,030217 neurology & neurosurgery - 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.
- Published
- 2020