Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy

Fuhrmann, Nico; Alavi, Marcel V.; Bitoun, Pierre; Woernle, S; Auburger, Georg; Leo-Kottler, Beate; Yu‐Wai‐Man, Patrick; Chinnery, Patrick F.; Wissinger, Bernd

doi:10.1136/jmg.2008.062570

Cited by 46 publications

(41 citation statements)

References 30 publications

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“…Our result is in agreement with the previous findings that indicated a high frequency of mutations involving genomic rearrangements. 25,36 Since we only conducted MLPA analysis in the patients with prenatal family history, the rate of OPA1 genomic DNA rearrangements might be underestimated.…”

Section: Discussionmentioning

confidence: 98%

Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Chen¹,

Xu²,

Zhang³

et al. 2014

Investigative Ophthalmology & Visual Science

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Section: Discussionmentioning

confidence: 98%

Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Chen¹,

Xu²,

Zhang³

et al. 2014

Investigative Ophthalmology & Visual Science

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“…The nuclear-encoded CAPN3, POLG, ANT1, PEO1, OPA1, RRM2B and POLG2 genes were sequenced by standard methods. The multiplex ligation-dependent probe amplification (MLPA) analysis for OPA1 rearrangements was performed as described [9]. The primer sequences for the POLG2 genomic DNA analysis are listed in Table 1. RNA analysis RNA was extracted from myoblasts and blood according to standard protocols (PAX Gene Blood RNA Kit, PreAnalytix/Qiagen, Hildesheim, Germany).…”

Section: Cell Culturementioning

confidence: 99%

Late-onset ptosis and myopathy in a patient with a heterozygous insertion in POLG2

et al. 2010

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Polymerase gamma 1 (POLG) mutations are a frequent cause of both autosomal dominant and recessive complex neurological phenotypes. In contrast, only a single pathogenic mutation in one patient was reported in POLG2 so far. Here we describe a 62-year-old woman, carrying a novel heterozygous sequence variant in the POLG2 gene. She developed bilateral ptosis at 30 years of age, followed by exercise intolerance, muscle weakness and mild CK increase in her late forties. Muscle histology and respiratory chain activities were normal. Southern blot and long range PCR detected multiple mtDNA deletions, but no depletion in muscle DNA. Sequencing of POLG, PEO1, ANT1, OPA1 and RRM2B showed normal results. A novel heteroallelic 24 bp insertion (c.1207_1208ins24) was detected in POLG2. This 24 bp insertion into exon 7 causes missplicing and loss of exon 7 in myoblast cDNA. We did not detect POLG2 mutations in 62 patients with multiple mtDNA deletions in muscle DNA, suggesting that POLG2 mutations may represent a rare cause of autosomal dominant PEO.

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“…Since OPA1 oligomerizes (48), mutations in the GED domain of one allele can complement mutations in the GTPase domain of another allele (64). Genomic rearrangements in OPA1 gene, as well as deletion of the entire one copy or part of the OPA1 gene have been reported (63,65,66), indicating haploinsufficiency as the main pathogenic mechanism. Overall, the majority of OPA1 mutations result in premature termination codons and unstable truncated mRNAs, which are degraded by protective surveillance mechanisms operating via nonsense-mediated mRNA decay (63,67,68), providing further evidence for haploinsufficiency.…”

Section: Mitochondrial Dynamic Proteins Related To the Pathogenesis Omentioning

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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Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy

Cited by 46 publications

References 30 publications

Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

Late-onset ptosis and myopathy in a patient with a heterozygous insertion in POLG2

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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