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.
authors.affiliation: Molecular Genetics Laboratory, University Eye Hospital, Tuebingen, Germany.
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bette
authors.forename: Simone
authors.initials: S
authors.lastname: Schimpf
authors.forename: Frank
authors.initials: F
authors.lastname: Schuettauf
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schraermeyer
authors.forename: Hans F
authors.initials: HF
authors.lastname: Wehrl
authors.forename: Lukas
authors.initials: L
authors.lastname: Ruttiger
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.forename: Felix
authors.initials: F
authors.lastname: Tonagel
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Thomas
authors.initials: T
authors.lastname: Peters
authors.forename: Juergen
authors.initials: J
authors.lastname: Laufs
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004270:DNA, Circular / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography / Q000379:methods; D005091:Exons / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006309:Hearing / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000235:genetics; D009154:Mutation / Q000235:genetics; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D022821:RNA Splice Sites / Q000235:genetics; D012160:Retina / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology; D012684:Sensory Thresholds / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000596:Amino Acids; D004270:DNA, Circular; D004272:DNA, Mitochondrial; D022821:RNA Splice Sites; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse