OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract

Reynier, Pascal; Amati‐Bonneau, Patrizia; Verny, Christophe; Olichon, Aurélien; Simard, Gilles; Guichet, Agnès; Bonnemains, C.; Malecaze, François; Malinge, Marie‐Claire; Pelletier, Jerry; Calvas, Patrick; Dollfus, Hélène; Bélenguer, Pascale; Malthièry, Yves; Lenaers, Guy; Bonneau, Dominique

doi:10.1136/jmg.2003.016576

Cited by 139 publications

(122 citation statements)

References 28 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…It is also possible that genetic heterogeneity accounts for the modest mutation detection rate, as four other genetic loci (OPA2, OPA3, OPA4, and OPA5) have been mapped that have been associated with Mendelian transmission of optic atrophy. [17][18][19] Also, the majority of the OPA1 mutations reported here were found in probands with a family history of ADOA, thus supporting the contention that OPA1 mutations are most often found in families with more than one affected individual. 16 However, singleton cases are not uncommon in ADOA.…”

Section: Discussionsupporting

confidence: 58%

“…3,5,15,16 Other genetic loci associated with Mendelian inherited optic atrophy have been mapped including two additional autosomal dominant (OPA4 and OPA5), a variable form that can be recessive or dominant with cataracts (OPA3), and an X-linked (OPA2) optic atrophy locus. [17][18][19] However, incomplete penetrance and variable expressivity is common even within ADOA families. Penetrance estimates range from roughly 40 -90%.…”

mentioning

confidence: 99%

See 1 more Smart Citation

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

Han¹,

Thompson-Lowrey²,

Reiss³

et al. 2006

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease. Methods: To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means. Results: Seven new pathogenic OPA1 mutations were found.Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus.Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients.Conclusions: Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases. Genet Med 2006:8(4):217-225.

show abstract

Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

Han¹,

Thompson-Lowrey²,

Reiss³

et al. 2006

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…Two different OPA3 mutations were found in exon 2: the c.277G>A (p.G93S) mutation and the c.313C>G (p.Q105E) mutation (Reynier et al, 2004). Both mutations segregated with the disease in each family and were absent in healthy relatives and in 400 control chromosomes.…”

Section: Opa3 Mutationsmentioning

confidence: 99%

“…OPA3 encodes a mitochondrial protein of unknown function located on the inner membrane (Da Cruz et al, 2003). We have found that dominant heterozygous mutations in OPA3 may be also responsible for an autosomal dominant form of optic atrophy associated with cataract (ADOAC) but without the presence of organic aciduria and neurological involvement (Reynier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

et al. 2009

View full text Add to dashboard Cite

ABSTRACT:We report the results of molecular screening in 980 patients carried out as part of their work-up for suspected hereditary optic neuropathies. All the patients were investigated for Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes, the two genes currently identified in ADOA. Molecular defects were identified in 440 patients (45% of screened patients). Among these, 295 patients (67%) had OFFICIAL JOURNAL www.hgvs.org E693 Molecular Screening of 980 Cases of Suspected Hereditary Optic Neuropathyan OPA1 mutation, 131 patients (30%) had an mtDNA mutation, and 14 patients (3%), belonging to three unrelated families, had an OPA3 mutation. Interestingly, OPA1 mutations were found in 157 (40%) of the 392 apparently sporadic cases of optic atrophy. The eOPA1 locus-specific database now contains a total of 204 OPA1 mutations, including 77 novel OPA1 mutations reported here. The statistical analysis of this large set of mutations has led us to propose a diagnostic strategy that should help with the molecular work-up of optic neuropathies. Our results highlight the importance of investigating LHON-causing mtDNA mutations as well as OPA1 and OPA3 mutations in cases of suspected hereditary optic neuropathy, even in absence of a family history of the disease.

show abstract

“…The three known 3-MGCA type III-related mutations are all assigned to exon 2 of OPA3A (157) and its adjacent splice site (146,149), while G93S and Q105E mutations lead to DOA associated with cataracts and extrapyramidal signs (158). Overexpression of a familial OPA3 mutant (G93S) induced mitochondrial fragmentation and spontaneous apoptosis, suggesting that OPA3 mutations may cause optic atrophy via a gain-of-function mechanism (156).…”

Section: Afg3l2 Heterozygous Missense Mutations In the Afg3l2mentioning

confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

View full text Add to dashboard Cite

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...

show abstract

OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract

Cited by 139 publications

References 28 publications

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Contact Info

Product

Resources

About