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At least 19 recordsLinked to original sources
PubMed2006

Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.

Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.

Adolescent↗
PubMed1995

No evidence of genetic heterogeneity in dominant optic atrophy.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease causing a variable reduction of visual acuity with an insidious onset in the first six years of life. It is associated with a central scotoma and an acquired blue-yellow dyschromatopsia. A gene for dominant optic atrophy (OPA1) has recently been mapped to chromosome 3q in three large Danish pedigrees. Here, we confirm the mapping of OPA1 to chromosome 3q28-qter by showing close linkage of the disease locus to three recently reported microsatellite DNA markers in the interval defined by loci D3S1314 and D3S1265 in four French families (Zmax = 5.13 at theta = 0 for probe AFM 308yf1 at locus D3S1601). Multipoint analysis supports the mapping of the disease gene to the genetic interval defined by loci D3S1314 and D3S1265. The present study provides three new markers closely linked to the disease gene for future genetic studies in OPA.

Chromosome Mapping↗
PubMed2005

Mitochondrial DNA content is decreased in autosomal dominant optic atrophy.

BACKGROUND: Autosomal dominant optic atrophy (ADOA) is the commonest form of inherited optic neuropathy. Mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein underlie ADOA and may perturb the biogenesis and maintenance of mitochondria. OBJECTIVE: To investigate the mutation spectrum of the OPA1 gene and assess alterations in mitochondrial content caused by OPA1 mutations. METHODS: Sixteen Korean patients with clinically suspected ADOA were studied. The mutation spectrum of the OPA1 gene was analyzed by PCR single-strand conformation polymorphism and sequencing, and mitochondrial DNA (mtDNA) content was quantified by real-time PCR. RESULTS: Eight different mutations were found, including five novel mutations. Quantitative real-time PCR analysis showed excellent linearity and precision for the determination of mtDNA copy numbers. The number of mtDNA copies per cell in patients with OPA1 gene mutations (ages 7 to 40) was significantly lower than those in all normal control subjects (p = 0.037), particularly lower than in normal control subjects ages 10 to 39 (p = 0.022). CONCLUSION: The mutation spectrum of the OPA1 gene disclosed marked genetic heterogeneity and the mitochondrial DNA content was found to be lower in autosomal dominant optic neuropathy, which provides direct evidence for a pathogenetic role of mutations of the OPA1 gene.

Adolescent↗
PubMed2006

Short wavelength-automated perimetry compared with standard achromatic perimetry in autosomal dominant optic atrophy.

BACKGROUND: Autosomal dominant optic atrophy (ADOA, Kjer-type) is a heterogeneous, non-inflammatory degeneration of retinal ganglion cells. The diagnosis of ADOA can be challenging owing to its insidious onset and large variability in phenotypic expression, both within and between individual pedigrees. The earliest literature reports relatively mild centrocaecal scatomas to white targets in ADOA, but extensive and dense peripheral field loss to coloured targets, especially blue, with Bjerrum perimetry. The phrase "inverted peripheral visual fields to coloured targets" has been used to describe this phenomenon. METHODS: Humphrey standard achromatic perimetry (SAP) and short wavelength-automated perimetry (SWAP) were carried out on five patients with ADOA. RESULTS: Regardless of wide variations in patient age, visual acuity, disc appearance and colour vision, the SWAP mean deviation (MD) was between 10 and 20 times more depressed than the SAP MD. The actual differences ranged from 9.38 to 13.78 dB. CONCLUSIONS: These data are consistent with the original reports suggesting that, early in this disease process, the blue-target deficits are typically peripheral and that this difference between SAP and SWAP perimetry may be a robust indicator of ADOA in both early and late stages of this disease.

Adolescent↗
PubMed2006

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy.

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 29 Caucasian 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.

Adolescent↗
PubMed2003

Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy.

BACKGROUND/AIMS: Patients with autosomal dominant optic atrophy (ADOA) are genetically heterogeneous, but all have disc pallor. A degree of cupping in ADOA can make the distinction from normal tension glaucoma (NTG) clinically difficult. This study aimed to clarify the features of the optic nerve of patients with ADOA at the OPA1 locus. METHODS: 29 patients (58 eyes), from 12 families, were identified in a prospective observational study of patients with ADOA examined by a single observer between 1995 and 1998, in whom genetic analysis showed either evidence for linkage to chromosome 3q28 or mutations in the ADOA gene, OPA1. All of the patients had disc and fundal photographs available for retrospective analysis. Clinical data collected included disc appearance, intraocular pressure, Snellen visual acuity, Hardy-Rand-Rittler colour vision plates, and Humphrey 30-2 visual fields. RESULTS: Mean age at time of examination was 37 years and mean visual acuity was 6/24. Disc morphology showed temporal disc pallor in 30 eyes (52%) and total disc pallor in 28 eyes (48%). At least one disc showed a cup to disc ratio of more than 0.5 in 18 patients (28 discs, 48%). The temporal neuroretinal rim always showed pallor and shallow shelving (or saucerisation) was seen in 46 eyes (79%). Only 12 discs (21%) had deep excavation and baring of blood vessels. All of the patients had normal intraocular pressure and no family history of glaucoma. There was a temporal grey, pigmentary crescent in 12 patients (18 eyes, 31%) and peripapillary atrophy in 20 patients (40 eyes, 69%), but disc margin haemorrhages were not seen. There was no maculopathy or retinopathy. CONCLUSION: The optic disc morphology, described for the first time in this genetically homogeneous population of patients with OPA1 ADOA, shows a distinctive absence of a healthy neuroretinal rim and shallow saucerisation of the optic disc cup, with frequent peripapillary atrophy.

Adolescent↗
PubMed1980

Autosomal dominant optic atrophy. A spectrum of disability.

Autosomal dominant optic atrophy is an abiotrophy with an insidious onset in the first decade of life. The clinical features of 31 individuals in six pedigrees are detailed in this study. These data suggest that here is considerable intrafamilial and interfamilial expression of dysfunction. Moreover, asymmetry of the visual loss in not unusual. An unexpected result of this study is the previously unreported frequent association of a neural hearing loss with this disorder.

Adolescent↗
PubMed2000

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

Amino Acid Sequence↗
PubMed1979

A clinicopathologic study of autosomal dominant optic atrophy.

Of a family with 40 members, 12 had autosomal dominant optic atrophy. The affected members were aware of reduced vision from the first decade. Visual loss was moderate to severe, 6/12 (20/40) to 3/60 (10/200). The affected members showed similar centrocecal scotomata. Most affected patients had severe unclassified color defects. Electroretinography measurements were normal in all but one patient who had a small reduction in the scotopic response. The pathologic changes in a patient with autosomal dominant optic atrophy showed diffuse atrophy of the ganglion cell layer of the retina with a loss of myelin and nerve tissue within the optic nerves. We suggest that autosomal dominant atrophy is a primary degeneration of retinal ganglion cells.

Adult↗
PubMed1985

Variable severity in autosomal dominant optic atrophy.

There are some indications in the literature on autosomal dominant optic atrophy that there are two genetic types - a congenital and a post-natal. This paper reviews the ocular findings of three affected members of a family with autosomal dominant optic atrophy - a father and two daughters - which appear to fit the criteria for a 'congenital' type of optic atrophy. Comparison with an additional 17 cases indicates that those with an early or congenital onset are at the more severe end of a distribution curve of involvement. The less severely affected patients were older and often had passed many years with little or no visual difficulties. Such variation is a recognized feature of autosomal dominant inheritance and is the basis for suggesting that there is probably only one genetic locus for autosomal dominant optic atrophy.

Adolescent↗
PubMed2005

OPA1, associated with autosomal dominant optic atrophy, is widely expressed in the human brain.

Autosomal dominant optic atrophy (adOA) is the most prevalent hereditary optic neuropathy with moderate to severe visual field loss and loss of retinal ganglion cells. The majority of cases of adOA is associated with mutations in the OPA1 gene. Northern blot analyses showed that OPA1 is expressed in all tissues examined, with the highest transcript level in the retina and in the brain. Here we addressed the cell type-specific expression of the OPA1 protein in human brain sections using immunohistochemical techniques and Western blotting. We studied OPA1 expression in normal cerebellum and various cerebral CNS tissue specimen of different areas obtained at autopsy from patients with no reported neurological symptoms or diseases and no neuropathological alterations using a polyclonal antibody raised against a C-terminal peptide of OPA1. We found OPA1 expression in somata and dendrites of neurons of the layers II-VI of the motor cortex and frontal brain. In the cerebellar cortex, OPA1 expression was detected in the Purkinje cell layer, in the granule cell layer and in the molecular layer. Double-labeling experiments showed also OPA1 expression in GFAP-positive astrocytes. Since mutations in the OPA1 gene specifically causes optic atrophy and occurrence of cerebral anomalies in adOA patients is not characteristic, this finding may suggest different cellular susceptibility of OPA1 in brain and retinal tissues.

Animals↗
PubMed2006

Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.

Adult↗
PubMed1986

Familial optic atrophy with sex-influenced severity. A new variety of autosomal-dominant optic atrophy?

A family is described with 20 members in three successive generations affected by optic atrophy without other ocular or extraocular manifestations. The anomaly was transmitted as an autosomal-dominant character. There was a clearly bimodal distribution of severity: 4 male patients complained of severe impairment of vision since childhood while 16 other subjects (7 males and 9 females) were completely asymptomatic. This family could be an example of a new variety of autosomal dominant optic atrophy characterized by sex-influenced severity.

Adolescent↗
PubMed2003

The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene.

PURPOSE: To examine the involvement of the optic atrophy 1 (OPA1) gene in optic atrophy associated with moderate deafness. DESIGN: Observational case report. The entire coding sequence of the OPA1 gene was directly sequenced in the case of a patient suffering from optic atrophy associated with moderate deafness. RESULTS: A de novo heterozygous mutation R445H in the OPA1 gene was found. No similar mutation was detected in either of the patient's parents or in the 100 chromosome controls. CONCLUSION: The R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed.

Adult↗
PubMed2003

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.

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). Sixty-nine 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.

Alternative Splicing↗
PubMed2000

MRI of the intraorbital optic nerve in patients with autosomal dominant optic atrophy.

Measurements of the intraorbital optic nerve were made using high-resolution coronal MRI in 10 adults with autosomal dominant optic atrophy. Comparisons were made with previous studies of 10 normal adult subjects. The cross-sectional diameters of the optic nerve and the perineural subarachnoid space were measured and a ratio of there diameters at anterior, mid and posterior positions along the optic nerve was determined. We found a statistically significant difference in the mean optic nerve: sheath ratio between the control group and patients with autosomal dominant optic atrophy. At anterior, mid and posterior locations along the optic nerve it is significantly smaller in patients with optic atrophy. We have demonstrated that the loss of ganglion cells, previously documented in dominant optic atrophy, is associated with a significant loss of optic nerve tissue and thinning of the nerve along its length.

Case-Control Studies↗