Table 1 - uploaded by Karen Grønskov
Content may be subject to copyright.
Source publication
Background
Investigation of the OPA1 mutation spectrum in autosomal dominant optic atrophy (ADOA) in Denmark.
Methods
Index patients from 93 unrelated ADOA families were assessed for a common Danish founder mutation (c.2826_2836delinsGGATGCTCCA) inOPA1. If negative, direct DNA sequencing of the coding sequence and multiplex ligation-dependent prob...
Contexts in source publication
Context 1
... analysis was performed analysing 14 SNP's surrounding the OPA1 gene (position chr3:188,391,767- 196,005,479, human genome version hg19/GRCh37) ( Table 1). The analysis was performed by KBiosciences (Hoddesdon, Herts, United Kingdom). ...
Context 2
... Glyfs*3). Haplotype analysis was performed using both affected and unaffected individuals from 10 families with c.983A > G and 10 families with c.2708_2711delT- TAG (Table 1). Nine out of 10 families with c.983A > G shared the same haplotype of size 1,8 Mb while one family had a different haplotype distal to OPA1. ...
Similar publications
Mutations in the human NPHP5 gene cause retinal and renal disease, but the precise mechanism by which NPHP5 functions is not understood. We report that
NPHP5 is a centriolar protein whose depletion inhibits an early step of ciliogenesis, a phenotype reminiscent of Cep290 loss
and contrary to IFT88 loss. Functional dissection of NPHP5 interactions w...
SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN).
Affected patients are wheelchair bound after 15 years old, with progressive joint contractures and spine deformities. SPOAN
patients also have sub normal vision secondary to apparently non-progressive congenital optic atr...
Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m‐AAA complex is an ATP‐dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m‐AAA subunits AFG3L2 and paraplegin are associated with au...
Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Two subgroups can be formed: isolated hereditary optic atrophies and optic neuropathy as part of complex disorders. In group 1 of hereditary optic neuropathies, optic nerve dysfunction is typically the only manifestation of the disease. This group...
Citations
... Although an increasing number of nuclear-encoded gene variants are being identified as the cause of DOA (20), 70%-90% of patients carry variants in the autosomal gene OPA1 (3q29, OMIM 605290) (21,22). The OPA1 gene is large, spanning .90 ...
... Three of these mutations, 3460G>A (ND1), 11778G>A (ND4) and 14484T>C (ND6), account for approximately 90 percent of cases [24][25][26]. DOA affects 1 in 12,000-25,000 people [27,28] and is predominantly due to mutations in the nuclear-encoded OPA1 gene [29,30]. This disrupts the finely tuned balance between mitochondrial fission and fusion resulting in deficits in cellular bioenergetics leading to RGC death [31,32]. ...
AAV gene therapy for ocular disease has become a reality with the market authorisation of LuxturnaTM for RPE65-linked inherited retinal degenerations and many AAV gene therapies currently undergoing phase III clinical trials. Many ocular disorders have a mitochondrial involvement from primary mitochondrial disorders such as Leber hereditary optic neuropathy (LHON), predominantly due to mutations in genes encoding subunits of complex I, to Mendelian and multifactorial ocular conditions such as dominant optic atrophy, glaucoma and age-related macular degeneration. In this study, we have optimised the nuclear yeast gene, NADH-quinone oxidoreductase (NDI1), which encodes a single subunit complex I equivalent, creating a candidate gene therapy to improve mitochondrial function, independent of the genetic mutation driving disease. Optimisation of NDI1 (ophNdi1) substantially increased expression in vivo, protected RGCs and increased visual function, as assessed by optokinetic and photonegative response, in a rotenone-induced murine model. In addition, ophNdi1 increased cellular oxidative phosphorylation and ATP production and protected cells from rotenone insult to a significantly greater extent than wild type NDI1. Significantly, ophNdi1 treatment of complex I deficient patient-derived fibroblasts increased oxygen consumption and ATP production rates, demonstrating the potential of ophNdi1 as a candidate therapy for ocular disorders where mitochondrial deficits comprise an important feature.
... Autosomal OA is a genetically heterogeneous, monogenic disorder, primarily caused by mutations in nuclear genes encoding mitochondrial proteins. Mutations in OPA1 are the most common cause of autosomal OA (Almind et al., 2012;Weisschuh et al., 2021). However, as discussed in detail below, mutations in at least 10 other genes are also associated with autosomal OA. ...
Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.
... DOA is genetically heterogeneous. Pathogenic variants in OPA1, which was the first gene to be described as an underlying cause of DOA [16][17][18][19][20][21][22][23], are found in 32-90% of DOA cases, depending on the population studied, the number of genes analyzed and the platform used. Other genes associated with DOA include WFS1 [24][25][26][27] . ...
... (278/755). This value is at the lower end of the range of 32-90% observed in other studies [18,23]. There are two possible explanations. ...
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.
... Pathogenic variants in OPA1 cause optic atrophy 1 (OMIM 165500), the most common form of autosomal dominant optic atrophy, affecting 1:10,000 to 1:40,000 people in the general population (Cohn et al. 2007;Yu-Wai-Man et al. 2010a;Almind et al. 2012). With the application of nextgeneration sequencing, a growing number of OPA1 variants was detected. ...
Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60–90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3′ terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.
... Depending on the population studied, 45-90% of DOA cases harbor pathogenic variants in OPA1 [6,7], which was the first gene to be described as an underlying cause of DOA [8,9]. OPA1 encodes a dynamin-related GTPase which is imported into mitochondria and plays an important role in mitochondrial dynamics and structural maintenance of the cristae junctions [10,11]. ...
... As of August 2020, the Human Gene Mutation Database (HGMD) lists 404 disease-causing variants in OPA1. Most variants are private and only few constitute founder alleles [7,12]. Overall, the majority of disease-causing variants are loss-of-function alleles, indicating that haploinsufficiency is the predominant disease mechanism underlying OPA1-linked DOA [12,13]. ...
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.
... The gene responsible for the 60-95% of cases is the Optic Atrophy 1, a nuclear gene that codes for a dynamin-related guanisine triphosphatase (GTPase) necessary for mitochondrial inner membrane fusion and maintenance of mitochondrial cristae architecture. Once again, the loss of this protein leads to mitochondrial dysfunction and cell apoptosis [54]. ...
Nutritional optic neuropathy is a cause of bilateral, symmetrical, and progressive visual impairment with loss of central visual acuity and contrast sensitivity, dyschromatopsia, and a central or centrocecal scotoma. The clinical features are not pathognomonic, since hereditary and toxic forms share similar signs and symptoms. It is becoming increasingly common due to the widespread of bariatric surgery and strict vegetarian or vegan diets, so even the scientific interest has recently increased. In particular, recent studies have focused on possible pathogenetic mechanisms, and on novel diagnostic and therapeutic strategies in order to prevent the onset, make a prompt diagnosis and an accurate nutritional supplementation, and to avoid irreversible optic nerve atrophy. Nowadays, there is clear evidence of the role of cobalamin, folic acid, thiamine, and copper, whereas further studies are needed to define the role of niacin, riboflavin, and pyridoxine. This review aims to summarize the etiology, diagnosis, and treatment of nutritional optic neuropathy, and it is addressed not only to ophthalmologists, but to all physicians who could come in contact with a patient with a possible nutritional optic neuropathy, being a fundamental multidisciplinary approach.
... Previously reported genes associated with autosomal recessive optic neuropathy all encode mitochondrial proteins. Transmembrane protein 126A (TMEM126A), which encodes for a mitochondrial inner membrane protein of unknown function, was the first gene to be found in autosomal recessive optic neuropathy (9,32). Aconitase 2 and reticulan 4-interacting protein 1 (RTN4IP1) are both involved in mitochondrial citric acid cycle (8,10) and also associated with autosomal recessive optic neuropathy. ...
Inherited optic neuropathies are rare eye diseases of optic nerve dysfunction that present in various genetic forms. Previously, mutation in three genes encoding mitochondrial proteins has been implicated in autosomal recessive forms of optic atrophy that involve progressive degeneration of optic nerve and retinal ganglion cells (RGC). Using whole exome analysis, a novel double homozygous mutation p.L81R and pR212W in malonyl CoA-acyl carrier protein transacylase (MCAT), a mitochondrial protein involved in fatty acid biosynthesis, has now been identified as responsible for an autosomal recessive optic neuropathy from a Chinese consanguineous family. MCAT is expressed in RGC that are rich in mitochondria. The disease variants lead to structurally unstable MCAT protein with significantly reduced intracellular expression. RGC-specific knockdown of Mcat in mice, lead to an attenuated retinal neurofiber layer, that resembles the phenotype of optic neuropathy. These results indicated that MCAT plays an essential role in mitochondrial function and maintenance of RGC axons, while novel MCAT p.L81R and p.R212W mutations can lead to optic neuropathy.
... Dominant optic atrophy (DOA) is the most common form of ION, with a prevalence of 1:12,000 to 1:50,000 (Lenaers et al. 2012;Yu-Wai-Man and Chinnery 2013). Mutations in the optic atrophy 1 gene (OPA1) are the main cause of disease, being found in 65-90% of DOA patients (Cohn et al. 2007;Almind et al. 2012;Chun and Rizzo 3rd 2016). Leber's hereditary optic neuropathy is the second most common type of ION, and is caused by mutations in the mitochondrial genome; it was found to have a prevalence of 1 in 35,000 in the north of England (Yu-Wai-Man et al. 2003;Yu-Wai-Man 2015;Jurkute et al. 2018). ...
Autosomal recessive optic neuropathies (IONs) are extremely rare disorders affecting retinal ganglion cells and the nervous system. RTN4IP1 has recently been identified as the third known gene associated with the autosomal recessive ION optic atrophy 10 (OPA10). Patients with RTN4IP1 mutations show early-onset optic neuropathy that can be followed by additional neurological symptoms such as seizures, ataxia, mental retardation, or even severe encephalopathy. Here, we report two siblings from a Chinese family who presented with early-onset optic neuropathy, epilepsy, and mild intellectual disability. Using whole exome sequencing combined with Sanger sequencing, we identified novel compound heterozygous RTN4IP1 mutations (c.646G > A, p.G216R and c.1162C > T, p.R388X) which both co-segregated with the disease phenotype and were predicted to be disease-causing by prediction software. An in vitro functional study in urine cells obtained from one of the patients revealed low expression of the RTN4IP1 protein. Our results identify novel compound heterozygous mutations in RTN4IP1 which are associated with OPA10, highlighting the frequency of RTN4IP1 mutations in human autosomal recessive IONs. To our knowledge, this is the first report of RTN4IP1 carriers from China.
... mechanisms responsible for OPA1-mediated optic neuropathy are only partially understood, and clinical studies of patients with mutations in OPA1 have been limited with respect to the clinical features examined [3,[5][6][7][8][9]19,20]. More than 300 independent disease-causing OPA1 variants have been characterized (Mitodyn) [21,22]. ...
... Overall, fewer mutations in OPA1 (32%) were found among patients in this sample compared to other studies (40-90% [3,[5][6][7][8][9];). Many of the previously published studies included only European populations with likely OPA1 founder effects, especially in Denmark [3]. ...
... Overall, fewer mutations in OPA1 (32%) were found among patients in this sample compared to other studies (40-90% [3,[5][6][7][8][9];). Many of the previously published studies included only European populations with likely OPA1 founder effects, especially in Denmark [3]. The rate of mutations in OPA1 in the present study is consistent with one other available study from the United States [9]. ...
Purpose
Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy.
Methods
Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing.
Results
Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative).
Conclusions
Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis.
