First report of OPA1 screening in Greek patients with autosomal dominant optic atrophy and identification of a previously undescribed OPA1 mutation (original) (raw)
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Novel OPA1 mutations identified in Japanese pedigrees with optic atrophy
Molecular vision
To determine whether mutations in the OPA1 gene were present in two Japanese families with optic atrophy. Thirty exons and their boundaries of the OPA1 gene were amplified by PCR with genomic DNA as templates and directly sequenced. The detected sequence changes were confirmed to be mutations by examining whether they were present in normal control individuals. A splicing mutation was characterized by RT-PCR of total RNA of leukocytes obtained from patients and one normal individual. The mutant transcripts resulting from the splicing mutation were further confirmed and quantified by sequencing and identifying the denatured RT-PCR products by polyacrylamide electrophoresis. One novel splicing mutation of c.871-1G>T and one novel insertion mutation of c.579_580insTT (p.R194fsX228) were identified from two familial cases, respectively. Both mutations segregated within the family heterozygously and were not found in the 189 control individuals examined. Two mutant transcripts resulte...
Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy
BMC Medical Genetics, 2011
Background: Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. Methods: Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA). When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. Results: Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. Conclusion: Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.
Journal of medical genetics, 1997
Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease characterised by variable optic atrophy and reduction in visual acuity. It has an insidious onset in the first decade oflife and is clinically highly heterogeneous. It is associated with a centrocecal scotoma ofvarying size and density and an acquired blue-yellow dyschromatopsia. Recent studies of three large Danish pedigrees have mapped a gene for dominant optic atrophy (OPAl) to a 10 cM region on chromosome 3q, between markers D3S1314 and D3S1265 (3q28-qter). Genetic linkage analysis in five British pedigrees confirms mapping to chromosome 3q28-qter. Haplotype analysis of a seven generation pedigree positions the disease causing gene between loci D3S3590 and D3S1305, corresponding to a genetic distance of 2 cM. This represents a significant linkage refinement and should facilitate positional cloning of the disease gene.
Human Molecular Genetics, 2001
We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.
Human Mutation, 2003
The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixtynine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3′-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.
Molecular Neurodegeneration, 2010
Background: Up to the 1950s, there was an ongoing debate about the diversity of hereditary optic neuropathies, in particular as to whether all inherited optic atrophies can be ascribed to Leber's hereditary optic neuropathy (LHON) or represent different disease entities. In 1954 W. Jaeger published a detailed clinical and genealogical investigation of a large family with explicit autosomal dominant segregation of optic atrophy thus proving the existence of a discrete disease different from LHON, which is nowadays known as autosomal dominant optic atrophy (ADOA). Since the year 2000 ADOA is associated with genomic mutations in the OPA1 gene, which codes for a protein that is imported into mitochondria where it is required for mitochondrial fusion. Interestingly enough, the underlying mutation in this family has not been identified since then.
Novel Mutations of the OPA1 Gene in Chinese Dominant Optic Atrophy
Ophthalmology, 2010
To investigate OPA1 gene mutations in Chinese patients with autosomal dominant optic atrophy and sporadic optic atrophy. Molecular genetic studies and observational case series. Twenty-four patients from 10 unrelated Chinese pedigrees of autosomal-dominant optic atrophy, 35 isolated cases with bilateral optic atrophy of unknown cause, and 50 unrelated normal controls. Genomic DNA was extracted from peripheral blood leukocytes. All 28 coding exons of the OPA1 gene and flanking intron splice sites were sequenced. Putative mutations were reexamined for segregation in the respective families by direct sequencing. Further characterization of selected splicing site mutations was performed by reverse transcription-polymerase chain reaction (PCR) of each patient's leukocyte mRNA. Direct sequencing of the OPA1 gene. Four OPA1 gene mutations were detected, including 2 splicing site mutations (c.1065+2T>C on intron 10 and c.1212+2insT on intron 12), 1 deletion (c.1776_1778delACT on exon 19), and 1 missense mutation (c.2846 T>C on exon 28). The c.1212+2insT, c.1776_1778delACT, and c.2846T>C mutations were newly identified OPA1 mutations. Reverse transcription (RT)-PCR and direct sequencing revealed that the splicing site mutations on c.1065+2T>C and c.1212+2insT caused skipping of exons 10 and 12, respectively. The c.1776_1778delACT mutation led to a deletion of the Leu amino acid on residue 593. OPA1 mutations were found in 4 of 10 familial cases (40 %) and in 1 of 35 sporadic cases of optic atrophy. OPA1 gene mutations are causative in Chinese autosomal-dominant optic atrophy and sporadic optic atrophy. Screening for OPA1 gene mutations in patients with childhood onset optic atrophy who have no affected relatives is useful in making the diagnosis.
Journal of the Neurological Sciences, 2017
Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n = 60) and Optical Coherence Tomography (OCT) (n = 12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G > A, and a new missense mutation, c1193A > C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from southeastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.
Ophthalmology, 2011
Purpose-Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. About 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have only been reported in two pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. Design-Retrospective case series. Participants-One hundred and eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomaldominant pattern of inheritance and 150 sporadic cases. Methods-OPA1 and OPA3 genetic testing was initially performed using PCR-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was further assessed with a targeted comparative genomic hybridization (CGH) microarray platform. The three primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G>A, m.11778G>A, and m.14484T>C, were also screened in all patients. Main Outcome Measures-The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases.