Journal Article

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

Marcel V. Alavi, Stefanie Bette, Simone Schimpf, Frank Schuettauf, Ulrich Schraermeyer, Hans F. Wehrl, Lukas Ruttiger, Susanne C. Beck, Felix Tonagel, Bernd J. Pichler, Marlies Knipper, Thomas Peters, Juergen Laufs and Bernd Wissinger

in Brain

Published on behalf of The Guarantors of Brain

Volume 130, issue 4, pages 1029-1042
Published in print April 2007 | ISSN: 0006-8950
Published online February 2007 | e-ISSN: 1460-2156 | DOI:
A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

Show Summary Details


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 ∼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: adOA; OPA1; splice site mutation; mitochondria; mouse model

Journal Article.  8184 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.