Improved Locus-Specific Database for<i>OPA1</i>Mutations Allows Inclusion of Advanced Clinical Data

Ferré, Marc; Caignard, Angélique; Miléa, Dan; Leruez, Stéphanie; Cassereau, Julien; Chevrollier, Arnaud; Amati‐Bonneau, Patrizia; Verny, Christophe; Bonneau, Dominique; Procaccio, Vincent; Reynier, Pascal

doi:10.1002/humu.22703

Cited by 43 publications

(45 citation statements)

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“…6 We also report an ADOA 'plus' patient due to a novel missense mutation c.892A4G (p.Ser298Gly) in exon 9, not previously reported. 6,7,28 This variant is predicted by the state of the art in silico methods to be disease causing with high confidence; (1) the substituted nucleic acid is highly conserved 29 (phyloP score: 4.88) leading to the substitution of a serine amino acid, which is highly conserved in the eight species aligned 30 in this study (Figure 2), (2) the main prediction tools for predicting damaging effects of missense mutations predict this mutation to affect the protein function with high confidence [31][32][33] (Mutation Taster probability: 0.99; Figure 1 Colour pupillometry in genetically confirmed ADOA patients. Dose-response curves for pupillary constriction are shown for controls (n = 54, filled circles) and patients with ADOA (n = 5, open circles), who were exposed to blue 469 nm light (a, left, blue trace) and red 631 nm light (b, right, red trace).…”

Section: Discussionmentioning

confidence: 99%

“…The mean ± SEM is shown in the graphs. PolyPhen-2 probability: 1.00; SIFT score: 0.00, with sequences used for prediction diverse enough), (3) we submitted the first report of this variant in the reference OPA1 locus-specific database 6,7 (DB-ID: OPA1_00306), and this mutation is unknown in the catalog of genome variations 34 and both in exome 35,36 or genome 37 databases of healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

“…mitodyn.org/), under our curation, has listed a total of 377 OPA1 gene variants, of which 65% are considered pathogenic. 6,7 The OPA1 gene, localized on 3q28-q29, has 30 coding exons including three alternative exons. It encodes a mitochondrial dynamin-related GTPase critical to mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

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Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

Loo

Singhal

Rukmini

et al. 2016

Eye

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

Loo

Singhal

Rukmini

et al. 2016

Eye

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“…Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3). It is generally diagnosed during childhood and is characterized by loss of visual acuity, dyschromatopsia, visual field defects and optic nerve pallor with optic disc excavation (4).…”

Section: Introductionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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Abstract.Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter-and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA. IntroductionAutosomal dominant optic atrophy (DOA) is a disorder that results from the degeneration of the optic nerve fibers (1). It is one of the most prevalent forms of inherited optic neuropathies, which are genetic conditions affecting the retinal ganglion cells whose axons constitute the optic nerve (2). DOA is an important cause of inherited visual failure and occurs equally among males and females (1). Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3). It is generally diagnosed during childhood and is characterized by loss of visual acuity, dyschromatopsia, visual field defects and optic nerve pallor with optic disc excavation (4).The majority of DOA cases (80%) are isolated (non-syndromic) while the remaining (20%) are syndromic (2). DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8). To date, 224 genes associated with optic atrophy are listed in the Human Phenotype Ontology (HPO) database, the majority presenting with neurological symptoms, such as ataxia, mental retardation and spastic paraplegia (9). Increasing evidence also indicates that other genes, in addition to yet unidentified genes, are involved (10). Yet, despite these advancements, more than half of DOA patients still await a genetic diagnosis (11). This shortcoming may be overcome using whole exome sequencing, which has the potential to define the molecular diagnosis of patients presenting with a negative result for mutations in the OPA1, OPA3, ACO2 and TMEM126A genes.In the current study, the exome of an Italian patient affected by isolated DOA was analyzed. By combining exome sequencing with phenotype-driven variant analysis, a heterozygous mutation was identified in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene. Notably, the p.R468C (c.1402C>T) mutation was recently described in a family ex...

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“…This OPA1 processing is reported to be regulated by several mitochondrial proteases including presenilin-associated rhomboid-like (PARL) (25), mitochondrial ATPases associated with diverse cellular activities (m-AAA) proteases (paraplegin and ATPase family gene 3-like protein 2-AFG3L2) (29), the mitochondrial inner membrane AAA (i-AAA) protease yeast mitochondrial escape (YME1)-like 1 ATPase (YME1L) and the membrane-bound metallopeptidase with activities overlapping with the m-AAA protease (OMA1) (30). Mutations in MFN2 and OPA1 gene were initially reported as being responsible for the rare neurodegenerative diseases Charcot-Marie-Tooth subtype 2A (CMT2A) and autosomal dominant optic atrophy (DOA), respectively (31,32). DRP1, the key player in fission, localizes primarily to the cytosol, but upon activation of mitochondrial fission, it is oligomerized and recruited by OMM-localized receptors, mainly mitochondrial fission factor (MFF) (18,33,34), mitochondrial division 49/51 (MiD49/51) (33), and less apparently mitochondrial fission 1 (FIS1) (18,33), to the OMM, where it forms high-molecular-weight protein complexes marking active or prospective fission sites (23).…”

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confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Improved Locus-Specific Database forOPA1Mutations Allows Inclusion of Advanced Clinical Data

Cited by 43 publications

References 47 publications

Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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