Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Charif, Majida; Chevrollier, Arnaud; Guéguen, Naïg; Bris, Céline; Goudenège, David; Desquiret-Dumas, Valérie; Leruez, Stéphanie; Colin, Estelle; Meunier, Audrey; Vignal, Catherine; Smirnov, Vasily; Defoort‐Dhellemmes, Sabine; Bouvet, Isabelle Drumare; Goizet, Cyril; Votruba, Marcela; Jurkutė, Neringa; Yu‐Wai‐Man, Patrick; Tagliavini, Fabrizio; Caporali, Leonardo; Morgia, Chiara La; Carelli, Valerio; Procaccio, Vincent; Zanlonghi, Xavier; Meunier, Isabelle; Reynier, Pascal; Bonneau, Dominique; Amati‐Bonneau, Patrizia; Lenaers, Guy

doi:10.1212/nxg.0000000000000428

Cited by 39 publications

(32 citation statements)

References 28 publications

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“…These candidate genes do not have a direct mitochondrial function, but these are selected after analysis of the WES data of other NOH patients by filtering with a list of 1,600 mitochondrial genes. Four primer pools (125- to 275-bp amplicon target sizes) were designed to amplify 313 and 274 amplicons, covering 22 genes ( Supplementary Table 1 ) ( 12 ) of a total length of 55.28 and 50.99 kb.…”

Section: Methodsmentioning

confidence: 99%

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Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

et al. 2021

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Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that OPA1 variants are responsible for the majority of dominant IONs, whereas ACO2 and WFS1 variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells.

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Section: Methodsmentioning

confidence: 99%

“…DOA is mainly caused by pathogenic OPA1 variants (8-10) and less frequently by mutations in other genes including OPA3, MFN2, SPG7, AFG3L2, DNM1L, and SSBP1 (11)(12)(13)(14)(15)(16)(17). These genes are all involved in controlling the mitochondrial dynamics, with the exception of SSBP1, which is involved in mtDNA replication.…”

Section: Introductionmentioning

confidence: 99%

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

et al. 2021

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“…The Qubit dsDNA High Sensitivity Assay Kit (Thermo Fisher Scientific) was used to quantify DNA for NGS library construction. Library preparation for each sample was performed using Ion AmpliSeq technologies, sequencing was undertaken using 540 ChIPs on Ion S5™ Sequencer using barcoded samples, and sequencing data was processed using our own dedicated bioinformatics pipeline as described elsewhere [ 31 , 32 ]. Within the design regions, 95% of bases had coverage over 100X, indicating that sufficient coverage was achieved to enable high variant detection sensitivity.…”

Section: Methodsmentioning

confidence: 99%

Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

Charif

Wong

Kim

et al. 2021

Mol Neurodegeneration

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Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration.

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“…Clinically phenocopies of LHON or DOA have been described in association with mutations in other nuclear genes, either recessive such as NDUFS2 [ 108 ], TMEM126A [ 109 , 110 ], RNT4IP1 [ 111 , 112 ] , SLC25A46 [ 113 ], ACO2 [ 114 ] , YME1L1 [ 115 ], or dominant as AFG3L2 and SPG7 [ 116 – 118 ], leading to isolated or syndromic HONs. Also, variable degrees of optic atrophy may be present along with other neurological and extra-neurological symptoms in other mtDNA-based mitochondrial encephalomyopathies, such as mitochondrial encephalopathy with ragged red fibres (MERRF), Leigh syndrome and mitochondrial encephalopathy with lactic acid and stroke-like episodes (MELAS) [ 1 , 2 , 6 ].…”

Section: Clinical Genetic and Biochemical Findings In Mitochondrialmentioning

confidence: 99%

Therapeutic Options in Hereditary Optic Neuropathies

Amore

Romagnoli

Carbonelli

et al. 2020

Drugs

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Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

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Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Cited by 39 publications

References 28 publications

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

Therapeutic Options in Hereditary Optic Neuropathies

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