Skip Navigation


Brain Advance Access originally published online on February 21, 2007
Brain 2007 130(4):1029-1042; doi:10.1093/brain/awm005
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
130/4/1029    most recent
awm005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (26)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Alavi, M. V.
Right arrow Articles by Wissinger, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alavi, M. V.
Right arrow Articles by Wissinger, B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Marcel V. Alavi1,*, Stefanie Bette1,*, Simone Schimpf1, Frank Schuettauf2, Ulrich Schraermeyer3, Hans F. Wehrl6, Lukas Ruttiger5, Susanne C. Beck4, Felix Tonagel4, Bernd J. Pichler6, Marlies Knipper5, Thomas Peters7, Juergen Laufs7 and Bernd Wissinger1

1Molecular Genetics Laboratory, 2Department of Pathophysiology of Vision and Neuro-Ophthalmology, 3Section for Experimental Vitreoretinal Surgery, University Eye Hospital, 4Retinal Diagnostics Research Group, University Eye Hospital, Tuebingen, 5Molecular Neurobiology, Tuebingen Hearing Research Center (THRC), Department of Otorhinolaryngology, University of Tuebingen, 6Laboratory for Preclinical Imaging and Imaging Technology, Department of Radiology and 7Ingenium Pharmaceuticals AG, Martinsried, Germany

Correspondence to: E-mail: wissinger{at}uni-tuebingen.de

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.

Key Words: adOA; OPA1; splice site mutation; mitochondria; mouse model

Abbreviations: adOA, autosomal dominant optic atrophy; ENU, N-ethyl-N-nitrosourea; MEFs, mouse embryonic fibroblasts; MRI, magnetic resonance imaging; OPA1, optic atrophy gene 1; RGC, retinal ganglion cell

.

Received August 25, 2006. Revised December 3, 2006. Accepted January 5, 2007.

*These authors contributed equally to this work.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
H. Chen and D. C. Chan
Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases
Hum. Mol. Genet., October 15, 2009; 18(R2): R169 - R176.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
J. Wakabayashi, Z. Zhang, N. Wakabayashi, Y. Tamura, M. Fukaya, T. W. Kensler, M. Iijima, and H. Sesaki
The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice
J. Cell Biol., September 21, 2009; 186(6): 805 - 816.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
D. C. Wallace and W. Fan
The pathophysiology of mitochondrial disease as modeled in the mouse
Genes & Dev., August 1, 2009; 23(15): 1714 - 1736.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
Z. Song, M. Ghochani, J. M. McCaffery, T. G. Frey, and D. C. Chan
Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion
Mol. Biol. Cell, August 1, 2009; 20(15): 3525 - 3532.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
M. Liesa, M. Palacin, and A. Zorzano
Mitochondrial Dynamics in Mammalian Health and Disease
Physiol Rev, July 1, 2009; 89(3): 799 - 845.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
P Yu-Wai-Man, P G Griffiths, G Hudson, and P F Chinnery
Inherited mitochondrial optic neuropathies
J. Med. Genet., March 1, 2009; 46(3): 145 - 158.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
W.-K. Ju, K.-Y. Kim, M. Angert, K. X. Duong-Polk, J. D. Lindsey, M. H. Ellisman, and R. N. Weinreb
Memantine Blocks Mitochondrial OPA1 and Cytochrome c Release and Subsequent Apoptotic Cell Death in Glaucomatous Retina
Invest. Ophthalmol. Vis. Sci., February 1, 2009; 50(2): 707 - 716.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
N Fuhrmann, M V Alavi, P Bitoun, S Woernle, G Auburger, B Leo-Kottler, P Yu-Wai-Man, P Chinnery, and B Wissinger
Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy
J. Med. Genet., February 1, 2009; 46(2): 136 - 144.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
C.-H. Cheng, T. Kikuchi, Y.-H. Chen, N. G. A.-A.-A. Sabbagha, Y.-C. Lee, H.-J. Pan, C. Chang, and Y.-T. Chen
Mutations in the SLC2A10 gene cause arterial abnormalities in mice
Cardiovasc Res, February 1, 2009; 81(2): 381 - 388.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
W.-K. Ju, K.-Y. Kim, J. D. Lindsey, M. Angert, K. X. Duong-Polk, R. T. Scott, J. J. Kim, I. Kukhmazov, M. H. Ellisman, G. A. Perkins, et al.
Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve
Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4903 - 4911.
[Abstract] [Full Text] [PDF]

Home page
 NeuroscientistHome page
R. H. Baloh
Mitochondrial Dynamics and Peripheral Neuropathy
Neuroscientist, February 1, 2008; 14(1): 12 - 18.
[Abstract] [PDF]

Home page
 BrainHome page
G. Hudson, P. Amati-Bonneau, E. L. Blakely, J. D. Stewart, L. He, A. M. Schaefer, P. G. Griffiths, K. Ahlqvist, A. Suomalainen, P. Reynier, et al.
Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance
Brain, February 1, 2008; 131(2): 329 - 337.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.