Skip Navigation


Human Molecular Genetics Advance Access originally published online on June 16, 2005
Human Molecular Genetics 2005 14(15):2099-2111; doi:10.1093/hmg/ddi215
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/15/2099    most recent
ddi215v1
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 (92)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Strauss, K. M.
Right arrow Articles by Krüger, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Strauss, K. M.
Right arrow Articles by Krüger, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease

Karsten M. Strauss1, L. Miguel Martins5, Helene Plun-Favreau6, Frank P. Marx1, Sabine Kautzmann1, Daniela Berg1,4, Thomas Gasser1, Zbginiew Wszolek7, Thomas Müller8, Antje Bornemann2, Hartwig Wolburg3, Julian Downward6, Olaf Riess4, Jörg B. Schulz1,*,{dagger} and Rejko Krüger1,{dagger}

1Center of Neurology and Hertie-Institute for Clinical Brain Research, 2Institute of Brain Research, 3Institute of Pathology and 4Department of Medical Genetics, University of Tübingen, Tübingen, Germany, 5MRC Toxicology Unit, Leicester, UK, 6Signal Transduction Laboratory, Cancer Research UK, London Research Institute, London, UK, 7Department of Neurology, Mayo Clinic, Jacksonville, FL, USA, 8Department of Neurology, Ruhr-University Bochum, Bochum, Germany and 9CMPB and Center of Neurology, University of Göttingen, Göttingen, Germany

* To whom correspondence should be addressed at: Department of Neurodegeneration and Restorative Research, Centers of Neurological Medicine and Molecular Physiology of the Brain, University of Göttingen, Waldweg 33, D-37073 Göttingen, Germany. Tel: +49 5513913540; Fax: +49 5513913541; Email: jschulz4{at}gwdg.de

Received February 26, 2005; Accepted June 7, 2005

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

{dagger} The 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
 Am. J. Physiol. Endocrinol. Metab.Home page
F. Fiory, P. Formisano, G. Perruolo, and F. Beguinot
Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism
Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E592 - E601.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
C. W. Olanow, M. B. Stern, and K. Sethi
The scientific and clinical basis for the treatment of Parkinson disease (2009)
Neurology, May 26, 2009; 72(21_Supplement_4): S1 - S136.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Lesage and A. Brice
Parkinson's disease: from monogenic forms to genetic susceptibility factors
Hum. Mol. Genet., April 15, 2009; 18(R1): R48 - R59.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Bras, J. Simon-Sanchez, M. Federoff, A. Morgadinho, C. Januario, M. Ribeiro, L. Cunha, C. Oliveira, and A. B. Singleton
Lack of replication of association between GIGYF2 variants and Parkinson disease
Hum. Mol. Genet., January 15, 2009; 18(2): 341 - 346.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
N. Padmanabhan, L. Fichtner, A. Dickmanns, R. Ficner, J. B. Schulz, and G. H. Braus
The Yeast HtrA Orthologue Ynm3 Is a Protease with Chaperone Activity that Aids Survival Under Heat Stress
Mol. Biol. Cell, January 1, 2009; 20(1): 68 - 77.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. Yun, J. H. Cao, M. W. Dodson, I. E. Clark, P. Kapahi, R. B. Chowdhury, and M. Guo
Loss-of-Function Analysis Suggests That Omi/HtrA2 Is Not an Essential Component of the pink1/parkin Pathway In Vivo
J. Neurosci., December 31, 2008; 28(53): 14500 - 14510.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Krick, S. Shi, W. Ju, C. Faul, S.-y. Tsai, P. Mundel, and E. P. Bottinger
Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease
PNAS, September 16, 2008; 105(37): 14106 - 14111.
[Abstract] [Full Text] [PDF]

Home page
 DMMHome page
A. J. Whitworth, J. R. Lee, V. M.-W. Ho, R. Flick, R. Chowdhury, and G. A. McQuibban
Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin
Dis. Model. Mech., September 1, 2008; 1(2-3): 168 - 174.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Simon-Sanchez and A. B. Singleton
Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls
Hum. Mol. Genet., July 1, 2008; 17(13): 1988 - 1993.
[Abstract] [Full Text] [PDF]

Home page
 Phil Trans R Soc BHome page
Y. Mizuno, N. Hattori, S.-i. Kubo, S. Sato, K. Nishioka, T. Hatano, H. Tomiyama, M. Funayama, Y. Machida, and H. Mochizuki
Progress in the pathogenesis and genetics of Parkinson's disease
Phil Trans R Soc B, June 27, 2008; 363(1500): 2215 - 2227.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Buttner, A. Bitto, J. Ring, M. Augsten, P. Zabrocki, T. Eisenberg, H. Jungwirth, S. Hutter, D. Carmona-Gutierrez, G. Kroemer, et al.
Functional Mitochondria Are Required for {alpha}-Synuclein Toxicity in Aging Yeast
J. Biol. Chem., March 21, 2008; 283(12): 7554 - 7560.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
C. Klein and M. G. Schlossmacher
Parkinson disease, 10 years after its genetic revolution: Multiple clues to a complex disorder
Neurology, November 27, 2007; 69(22): 2093 - 2104.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. J. Huttunen, S. Y. Guenette, C. Peach, C. Greco, W. Xia, D. Y. Kim, C. Barren, R. E. Tanzi, and D. M. Kovacs
HtrA2 Regulates beta-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation
J. Biol. Chem., September 21, 2007; 282(38): 28285 - 28295.
[Abstract] [Full Text] [PDF]

Home page
 DNA ResHome page
D. Gherbassi, L. Bhatt, S. Thuret, and H. H. Simon
Merging Mouse Transcriptome Analyses with Parkinson's Disease Linkage Studies
DNA Res, May 23, 2007; (2007) dsm007v1.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
W. Mandemakers, V. A. Morais, and B. De Strooper
A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases
J. Cell Sci., May 15, 2007; 120(10): 1707 - 1716.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
K. Tagawa, S. Marubuchi, M.-L. Qi, Y. Enokido, T. Tamura, R. Inagaki, M. Murata, I. Kanazawa, E. E. Wanker, and H. Okazawa
The Induction Levels of Heat Shock Protein 70 Differentiate the Vulnerabilities to Mutant Huntingtin among Neuronal Subtypes
J. Neurosci., January 24, 2007; 27(4): 868 - 880.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
G. Kroemer, L. Galluzzi, and C. Brenner
Mitochondrial Membrane Permeabilization in Cell Death
Physiol Rev, January 1, 2007; 87(1): 99 - 163.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
E.-K. Tan and J. Jankovic
Genetic testing in Parkinson disease: promises and pitfalls.
Arch Neurol, September 1, 2006; 63(9): 1232 - 1237.
[Full Text] [PDF]

Home page
 Arch NeurolHome page
M. M. K. Muqit, S. Gandhi, and N. W. Wood
Mitochondria in Parkinson disease: back in fashion with a little help from genetics.
Arch Neurol, May 1, 2006; 63(5): 649 - 654.
[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.