Research ExplorerPublicationsA splice site mutation in the murine Opa1 gene features path...

A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

Standard

A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. / Alavi, Marcel V; Bette, Stefanie; Schimpf, Simone; Schuettauf, Frank; Schraermeyer, Ulrich; Wehrl, Hans F; Ruttiger, Lukas; Beck, Susanne C; Tonagel, Felix; Pichler, Bernd J; Knipper, Marlies; Peters, Thomas; Laufs, Juergen; Wissinger, Bernd.

In: BRAIN, Vol. 130, No. Pt 4, 04.2007, p. 1029-42.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Alavi, MV, Bette, S, Schimpf, S, Schuettauf, F, Schraermeyer, U, Wehrl, HF, Ruttiger, L, Beck, SC, Tonagel, F, Pichler, BJ, Knipper, M, Peters, T, Laufs, J & Wissinger, B 2007, 'A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy', BRAIN, vol. 130, no. Pt 4, pp. 1029-42. https://doi.org/10.1093/brain/awm005

APA

Alavi, M. V., Bette, S., Schimpf, S., Schuettauf, F., Schraermeyer, U., Wehrl, H. F., Ruttiger, L., Beck, S. C., Tonagel, F., Pichler, B. J., Knipper, M., Peters, T., Laufs, J., & Wissinger, B. (2007). A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. BRAIN, 130(Pt 4), 1029-42. https://doi.org/10.1093/brain/awm005

Vancouver

Alavi MV, Bette S, Schimpf S, Schuettauf F, Schraermeyer U, Wehrl HF et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. BRAIN. 2007 Apr;130(Pt 4):1029-42. https://doi.org/10.1093/brain/awm005

Bibtex

@article{3266eda51b044f3aa2d49b6b023b7b63,
title = "A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy",
abstract = "Autosomal dominant optic atrophy (adOA) is a juvenile onset, progressive ocular disorder characterized by bilateral loss of vision, central visual field defects, colour vision disturbances, and optic disc pallor. adOA is most frequently associated with mutations in OPA1 encoding a dynamin-related large GTPase that localizes to mitochondria. Histopathological studies in adOA patients have shown a degeneration of retinal ganglion cells (RGCs) and a loss of axons in the optic nerve. However little is known about the molecular mechanism and pathophysiology of adOA due to the lack of appropriate in vivo models. Here we report a first mouse model carrying a splice site mutation (c.1065 + 5G --> A) in the Opa1 gene. The mutation induces a skipping of exon 10 during transcript processing and leads to an in-frame deletion of 27 amino acid residues in the GTPase domain. Western blot analysis showed no evidence of a shortened mutant protein but a approximately 50% reduced OPA1 protein level supporting haploinsufficiency as a major disease mechanism in adOA. Homozygous mutant mice die in utero during embryogenesis with first notable developmental delay at E8.5 as detected by magnetic resonance imaging (MRI). Heterozygous mutants are viable and of normal habitus but exhibit an age-dependent loss of RGCs that eventually progresses to a severe degeneration of the ganglion cell and nerve fibre layer. In addition optic nerves of mutant mice showed a reduced number of axons, and a swelling and abnormal shape of the remaining axons. Mitochondria in these axons showed disorganized cristae structures. All these defects recapitulate crucial features of adOA in humans and therefore document the validity and importance of this model for future research.",
keywords = "Amino Acids/genetics, Animals, Cells, Cultured, DNA, Circular/genetics, DNA, Mitochondrial/genetics, Disease Models, Animal, Electroretinography/methods, Exons/genetics, GTP Phosphohydrolases/genetics, Hearing/genetics, Magnetic Resonance Imaging/methods, Mice, Mice, Inbred C3H, Microscopy, Electron, Transmission/methods, Mitochondria/genetics, Mutation/genetics, Optic Atrophy, Autosomal Dominant/genetics, Optic Nerve/pathology, RNA Splice Sites/genetics, Retina/pathology, Retinal Ganglion Cells/pathology, Sensory Thresholds/physiology, Transcription, Genetic/genetics",
author = "Alavi, {Marcel V} and Stefanie Bette and Simone Schimpf and Frank Schuettauf and Ulrich Schraermeyer and Wehrl, {Hans F} and Lukas Ruttiger and Beck, {Susanne C} and Felix Tonagel and Pichler, {Bernd J} and Marlies Knipper and Thomas Peters and Juergen Laufs and Bernd Wissinger",
year = "2007",
month = apr,
doi = "10.1093/brain/awm005",
language = "English",
volume = "130",
pages = "1029--42",
journal = "BRAIN",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "Pt 4",

}

RIS

TY - JOUR

T1 - A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

AU - Alavi, Marcel V

AU - Bette, Stefanie

AU - Schimpf, Simone

AU - Schuettauf, Frank

AU - Schraermeyer, Ulrich

AU - Wehrl, Hans F

AU - Ruttiger, Lukas

AU - Beck, Susanne C

AU - Tonagel, Felix

AU - Pichler, Bernd J

AU - Knipper, Marlies

AU - Peters, Thomas

AU - Laufs, Juergen

AU - Wissinger, Bernd

PY - 2007/4

Y1 - 2007/4

N2 - Autosomal dominant optic atrophy (adOA) is a juvenile onset, progressive ocular disorder characterized by bilateral loss of vision, central visual field defects, colour vision disturbances, and optic disc pallor. adOA is most frequently associated with mutations in OPA1 encoding a dynamin-related large GTPase that localizes to mitochondria. Histopathological studies in adOA patients have shown a degeneration of retinal ganglion cells (RGCs) and a loss of axons in the optic nerve. However little is known about the molecular mechanism and pathophysiology of adOA due to the lack of appropriate in vivo models. Here we report a first mouse model carrying a splice site mutation (c.1065 + 5G --> A) in the Opa1 gene. The mutation induces a skipping of exon 10 during transcript processing and leads to an in-frame deletion of 27 amino acid residues in the GTPase domain. Western blot analysis showed no evidence of a shortened mutant protein but a approximately 50% reduced OPA1 protein level supporting haploinsufficiency as a major disease mechanism in adOA. Homozygous mutant mice die in utero during embryogenesis with first notable developmental delay at E8.5 as detected by magnetic resonance imaging (MRI). Heterozygous mutants are viable and of normal habitus but exhibit an age-dependent loss of RGCs that eventually progresses to a severe degeneration of the ganglion cell and nerve fibre layer. In addition optic nerves of mutant mice showed a reduced number of axons, and a swelling and abnormal shape of the remaining axons. Mitochondria in these axons showed disorganized cristae structures. All these defects recapitulate crucial features of adOA in humans and therefore document the validity and importance of this model for future research.

AB - Autosomal dominant optic atrophy (adOA) is a juvenile onset, progressive ocular disorder characterized by bilateral loss of vision, central visual field defects, colour vision disturbances, and optic disc pallor. adOA is most frequently associated with mutations in OPA1 encoding a dynamin-related large GTPase that localizes to mitochondria. Histopathological studies in adOA patients have shown a degeneration of retinal ganglion cells (RGCs) and a loss of axons in the optic nerve. However little is known about the molecular mechanism and pathophysiology of adOA due to the lack of appropriate in vivo models. Here we report a first mouse model carrying a splice site mutation (c.1065 + 5G --> A) in the Opa1 gene. The mutation induces a skipping of exon 10 during transcript processing and leads to an in-frame deletion of 27 amino acid residues in the GTPase domain. Western blot analysis showed no evidence of a shortened mutant protein but a approximately 50% reduced OPA1 protein level supporting haploinsufficiency as a major disease mechanism in adOA. Homozygous mutant mice die in utero during embryogenesis with first notable developmental delay at E8.5 as detected by magnetic resonance imaging (MRI). Heterozygous mutants are viable and of normal habitus but exhibit an age-dependent loss of RGCs that eventually progresses to a severe degeneration of the ganglion cell and nerve fibre layer. In addition optic nerves of mutant mice showed a reduced number of axons, and a swelling and abnormal shape of the remaining axons. Mitochondria in these axons showed disorganized cristae structures. All these defects recapitulate crucial features of adOA in humans and therefore document the validity and importance of this model for future research.

KW - Amino Acids/genetics

KW - Animals

KW - Cells, Cultured

KW - DNA, Circular/genetics

KW - DNA, Mitochondrial/genetics

KW - Disease Models, Animal

KW - Electroretinography/methods

KW - Exons/genetics

KW - GTP Phosphohydrolases/genetics

KW - Hearing/genetics

KW - Magnetic Resonance Imaging/methods

KW - Mice

KW - Mice, Inbred C3H

KW - Microscopy, Electron, Transmission/methods

KW - Mitochondria/genetics

KW - Mutation/genetics

KW - Optic Atrophy, Autosomal Dominant/genetics

KW - Optic Nerve/pathology

KW - RNA Splice Sites/genetics

KW - Retina/pathology

KW - Retinal Ganglion Cells/pathology

KW - Sensory Thresholds/physiology

KW - Transcription, Genetic/genetics

U2 - 10.1093/brain/awm005

DO - 10.1093/brain/awm005

M3 - SCORING: Journal article

C2 - 17314202

VL - 130

SP - 1029

EP - 1042

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - Pt 4

ER -