A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy
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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, Jahrgang 130, Nr. Pt 4, 04.2007, S. 1029-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -