Molecular genetic basis of primary inherited optic neuropathies

Votruba, Marcela

doi:10.1038/sj.eye.6701570

Cited by 53 publications

(35 citation statements)

References 65 publications

(61 reference statements)

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“…The disorder is due to cell death confined to retinal ganglion cells which results in bilateral central visual loss, impaired color vision and central visual field defects [1,2]. The prevalence of ADOA is estimated to be between 1/50,000 and 1/10,000 [3,4].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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The most frequent form of hereditary blindness, Autosomal Dominant Optic Atrophy (ADOA) is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca 2+ uptake (Fülöp et al.,PLoS One 2011). Therefore we studied mitochondrial Ca 2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell -inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca 2+ signals. The present data indicate that enhanced mitochondrial Ca 2+ uptake is a pathogenetic factor in the progress of ADOA.3

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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“…DOA is one of the most common forms of inherited optic neuropathy with an incidence of 1:12,000 to 1:50,000 (Votruba et al, 2003) and mutation of OPA1 is one of the most common genetic causes. OPA1 protein is a dynamin-related GTPase, encoded by the nuclear genome, but localized to the inner membrane of the mitochondria, and is ubiquitously expressed (Alexander et al, 2000;Delettre et al, 2000;Misaka et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…OPA1 mutations lead to fragmentation of mitochondria, decreased ATP production and increased oxygen reactive species (Tang et al, 2009;Lodi et al, 2004). Optic nerve degeneration in OPA1 mutations is considered to be secondary to their effect on retinal ganglion cells and not to involve rods and cones or bipolar cells (Votruba et al, 2003). Axons of ganglion cells within the retina are unmyelinated, of small diameter, and contain numerous mitochondria that provide energy for transmitting graded neural potentials.…”

Section: Introductionmentioning

confidence: 99%

Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals

2009

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Autosomal dominant optic atrophy (DOA) is a retinal neuronal degenerative disease characterized by a progressive bilateral visual loss. We report on two affected members of a family with dominantly inherited neuropathy of both optic and auditory nerves expressed by impaired visual acuity, moderate pure tone hearing loss, and marked loss of speech perception. We investigated cochlear abnormalities accompanying the hearing loss and the effects of cochlear implantation. We sequenced OPA1 gene and recorded cochlear receptor and neural potentials before cochlear implantation. Genetic analysis identified R445H mutation in OPA1 gene. Audiological studies showed preserved cochlear receptor outer hair cell activities (otoacoustic emissions) and absent or abnormally delayed auditory brainstem responses (ABRs). Trans-tympanic electrocochleography (ECochG) showed prolonged low amplitude negative potentials without auditory nerve compound action potentials. The latency of onset of the cochlear potentials was within the normal range found for inner hair cell summating receptor potentials. The duration of the negative potential was reduced to normal during rapid stimulation consistent with adaptation of neural sources generating prolonged cochlear potentials. Both subjects had cochlear implants placed with restoration of hearing thresholds, speech perception, and synchronous activity in auditory brainstem pathways. The results suggest that deafness accompanying this OPA1 mutation is due to altered function of terminal unmyelinated portions of auditory nerve. Electrical stimulation of the cochlea activated proximal myelinated portions of auditory nerve to restore hearing

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“…5). This is a crucial point since the number of optic atrophies associated with mutation of mitochondrial proteins is rapidly growing (47,48). Furthermore, the importance of accurately controlled mitochondrial dynamics in neuronal cells is becoming increasingly well documented.…”

Section: Effects Of Opa1 Pathogenic Alleles On Cellmentioning

confidence: 99%

Effects of OPA1 mutations on mitochondrial morphology and apoptosis: Relevance to ADOA pathogenesis

Olichon

Landes

Arnauné-Pelloquin

et al. 2006

Journal Cellular Physiology

124

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Molecular genetic basis of primary inherited optic neuropathies

Abstract: Aim To review the molecular genetic basis of primary inherited optic neuropathies. Methods Medline and Embase search.

Cited by 53 publications

References 65 publications

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals

Effects of OPA1 mutations on mitochondrial morphology and apoptosis: Relevance to ADOA pathogenesis

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