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ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

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.

SUBMITTER: Caporali L

PROVIDER: S-EPMC7383914 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

Caporali Leonardo L Magri Stefania S Legati Andrea A Del Dotto Valentina V Tagliavini Francesca F Balistreri Francesca F Nasca Alessia A La Morgia Chiara C Carbonelli Michele M Valentino Maria L ML Lamantea Eleonora E Baratta Silvia S Schöls Ludger L Schüle Rebecca R Barboni Piero P Cascavilla Maria L ML Maresca Alessandra A Capristo Mariantonietta M Ardissone Anna A Pareyson Davide D Cammarata Gabriella G Melzi Lisa L Zeviani Massimo M Peverelli Lorenzo L Lamperti Costanza C Marzoli Stefania B SB Fang Mingyan M Synofzik Matthis M Ghezzi Daniele D Carelli Valerio V Taroni Franco F

Annals of neurology 20200421 1

<h4>Objective</h4>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.<h4>Methods</h4>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-d ...[more]

PMID: 32219868

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Project description:Leber hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. These mtDNA pathogenic mutations have variable clinical penetrance. Recent linkage evidence raised the possibility that the nuclear gene optic atrophy 1 (OPA1) determines whether mtDNA mutation carriers develop blindness. To validate these findings we studied OPA1 in three independent LHON cohorts: sequencing the gene in discordant male sib pairs, carrying out a family-based association study of common functional genetic variants, and carrying out a population-based association study of the same genetic variants.We tested 3 hypothesis in three separate study groups. Study group 1: Direct sequencing of OPA1 coding regions was performed using sequencing methodologies (Applied Biosystems, Foster City, CA). Chromatograms were compared with the GenBank reference sequence NM_015560.1. Splice-site prediction was performed using GeneSplicer. Study group 2: Genotyping for rs166850 and rs10451941 was performed by restriction fragment length polymorphism (RFLP) analysis with specific primers for both genotypes, using The restriction enzymes RsaI and FspBI to discriminate genotypes. Study group 3: Genotyping for rs166850 and rs10451941 was performed by primer extension of allele-specific extensions products by matrix-associated laser desorption/ionisation time-of-flight (MALDI-TOF, Seqeunom, San Diego, CA) mass spectrometry. Allele and genotype frequencies were compared using Pearson's chi-square test. Multiple logistic regression was performed to look for interactions between the variables. All analyses were performed using SPSS software version 17.0 (SPSS Inc.).In all three groups we were unable to find an association between OPA1 genetic variation and visual failure in LHON mtDNA mutation carriers.Our findings suggest that genetic variation in OPA1 is unlikely to make a major contribution to the risk of blindness in LHON mutation carriers.

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ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

Publications

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

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