First submicroscopic inversion of the OPA1 gene identified in dominant optic atrophy – a case report

Abstract Background Dominant optic atrophy (DOA) is an inherited optic neuropathy that mainly affects visual acuity, central visual fields and color vision due to a progressive loss of retinal ganglion cells and their axons that form the optic nerve. Approximately 45–90% of affected individuals with DOA harbor pathogenic variants in the OPA1 gene. The mutation spectrum of OPA1 comprises nonsense, canonical and non-canonical splice site, frameshift and missense as well as copy number variants, but intragenic inversions have not been reported so far. Case presentation We report a 33-year-old male with characteristic clinical features of DOA. Whole-genome sequencing identified a structural variant of 2.4 kb comprising an inversion of 937 bp at the OPA1 locus. Fine mapping of the breakpoints to single nucleotide level revealed that the structural variation was an inversion flanked by two deletions. As this rearrangement inverts the entire first exon of OPA1, it was classified as likely pathogenic. Conclusions We report the first DOA case harboring an inversion in the OPA1 gene. Our study demonstrates that copy-neutral genomic rearrangements have to be considered as a possible cause of disease in DOA cases.

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OPA1 Deficiency Associated with Increased Autophagy in Retinal Ganglion Cells in a Murine Model of Dominant Optic Atrophy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.08-2913 ◽

2009 ◽

Vol 50 (6) ◽

pp. 2567 ◽

Cited By ~ 59

Author(s):

Kathryn E. White ◽

Vanessa J. Davies ◽

Vanessa E. Hogan ◽

Malgorzata J. Piechota ◽

Philip P. Nichols ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Murine Model ◽

Optic Atrophy ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Dominant Optic Atrophy

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Dendritic pruning of retinal ganglion cells in a mouse model of dominant optic atrophy (ADOA)

Acta Ophthalmologica ◽

10.1111/j.1755-3768.2010.2345.x ◽

2010 ◽

Vol 88 ◽

pp. 0-0

Author(s):

M VOTRUBA ◽

P WILLIAMS ◽

JE MORGAN

Keyword(s):

Mouse Model ◽

Retinal Ganglion Cells ◽

Optic Atrophy ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Dominant Optic Atrophy

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Dominant ACO2 mutations are a frequent cause of isolated optic atrophy

Brain Communications ◽

10.1093/braincomms/fcab063 ◽

2021 ◽

Author(s):

Majida Charif ◽

Naïg Gueguen ◽

Marc Ferré ◽

Zouhair Elkarhat ◽

Salim Khiati ◽

...

Keyword(s):

Optic Atrophy ◽

Ganglion Cells ◽

Krebs Cycle ◽

Dna Amount ◽

Dominant Optic Atrophy ◽

Pathogenic Variants ◽

Mitochondrial Aconitase ◽

Krebs Cycle Intermediates ◽

Biallelic Mutations ◽

First Time

Abstract Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harboring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harboring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells. By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, Charif et al. report 61 new cases harboring variants in ACO2, among whom 50 with dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy.

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OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Scientific Reports ◽

10.1038/s41598-018-20838-8 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 15

Author(s):

Emmanuelle Sarzi ◽

Marie Seveno ◽

Camille Piro-Mégy ◽

Lucie Elzière ◽

Mélanie Quilès ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Optic Atrophy ◽

Cell Loss ◽

Retinal Ganglion ◽

Dominant Optic Atrophy ◽

Opa1 Gene

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Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

PLoS ONE ◽

10.1371/journal.pone.0253987 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0253987

Author(s):

Nicole Weisschuh ◽

Simone Schimpf-Linzenbold ◽

Pascale Mazzola ◽

Sinja Kieninger ◽

Ting Xiao ◽

...

Keyword(s):

Genetic Testing ◽

Optic Atrophy ◽

Copy Number Variations ◽

Large Cohort ◽

Mutation Spectrum ◽

Genetic Diagnostics ◽

Dominant Optic Atrophy ◽

Pathogenic Variants ◽

Opa1 Gene ◽

Novel Variants

Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the OPA1 gene: depending on the population studied, 32–90% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the OPA1 gene in a large cohort of patients. Over a period of 20 years, 755 unrelated probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the OPA1 gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the OPA1 gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered null alleles. Variant c.2708_2711del/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients´ blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.

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A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

Brain ◽

10.1093/brain/awm005 ◽

2006 ◽

Vol 130 (4) ◽

pp. 1029-1042 ◽

Cited By ~ 143

Author(s):

M. V. Alavi ◽

S. Bette ◽

S. Schimpf ◽

F. Schuettauf ◽

U. Schraermeyer ◽

...

Keyword(s):

Splice Site ◽

Optic Atrophy ◽

Autosomal Dominant ◽

Splice Site Mutation ◽

Site Mutation ◽

Autosomal Dominant Optic Atrophy ◽

Dominant Optic Atrophy ◽

Opa1 Gene

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Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy

Cell Death and Differentiation ◽

10.1038/s41418-021-00847-3 ◽

2021 ◽

Author(s):

Marta Zaninello ◽

Konstantinos Palikaras ◽

Aggeliki Sotiriou ◽

Nektarios Tavernarakis ◽

Luca Scorrano

Keyword(s):

Mitochondrial Dysfunction ◽

Motor Neurons ◽

Optic Atrophy ◽

Autosomal Dominant ◽

Ganglion Cells ◽

Mitochondrial Dynamics ◽

Second Messengers ◽

Mitochondrial Density ◽

Autosomal Dominant Optic Atrophy ◽

Dominant Optic Atrophy

AbstractMitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.

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