Document Detail

A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function.
MedLine Citation:
PMID:  18678599     Owner:  NLM     Status:  MEDLINE    
Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed as possible causal factors. However, their relative contribution to pathogenesis as well as the prominent susceptibility of the retinal ganglion cell (RGC) in this disease remains uncertain. Here we identify a novel deletion of OPA1 gene in the GTPase domain in three patients affected by ADOA. Muscle biopsy of the patients showed neurogenic atrophy and abnormal morphology and distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts as well as in myotubes, where mitochondria were also unevenly distributed, with clustered organelles alternating with areas where mitochondria were sparse. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro-apoptotic stimuli. Therefore, changes in mitochondrial shape and distribution can be independent of other reported effects of OPA1 mutations, and therefore may be the primary cause of the disease. The arrangement of mitochondria in RGCs, which degenerate in ADOA, may be exquisitely sensitive to disturbance, and this may lead to bioenergetic crisis and/or induction of apoptosis. Our results highlight the importance of mitochondrial dynamics in the disease per se, and point to the loss of the fine positioning of mitochondria in the axons of RGCs as a possible explanation for their predominant degeneration in ADOA.
Marco Spinazzi; Silvia Cazzola; Mario Bortolozzi; Alessandra Baracca; Emanuele Loro; Alberto Casarin; Giancarlo Solaini; Gianluca Sgarbi; Gabriella Casalena; Giovanna Cenacchi; Adriana Malena; Christian Frezza; Franco Carrara; Corrado Angelini; Luca Scorrano; Leonardo Salviati; Lodovica Vergani
Related Documents :
9781049 - Refined mapping of the gene encoding the p127 kda uv-damaged dna-binding protein (ddb1)...
17761649 - Spinal muscular atrophy diagnostics.
7665169 - Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dyst...
22034999 - A genome-wide association study of direct gestation length in us holstein and italian b...
7910579 - Pulsed-field gel electrophoresis of the d4f104s1 locus reveals the size and the parenta...
16603329 - The mildest known case of fukuyama-type congenital muscular dystrophy.
16777709 - Cytotoxicity and genotoxicity induced by the pesticide profenofos on cultured human per...
24371769 - Two copies of isochromosome 5p in refractory cytopenia with multilineage dysplasia: a c...
3539379 - The technique of premature chromosome condensation to study the leukemic process: revie...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-08-04
Journal Detail:
Title:  Human molecular genetics     Volume:  17     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-13     Completed Date:  2009-02-10     Revised Date:  2012-04-11    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  3291-302     Citation Subset:  IM    
Neurosciences Department, University of Padova, Italy.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Cells, Cultured
Energy Metabolism
GTP Phosphohydrolases / genetics*,  metabolism
Gene Expression Regulation, Enzymologic
Middle Aged
Mitochondria / metabolism*,  pathology
Muscle, Skeletal / abnormalities,  enzymology
Optic Atrophy, Autosomal Dominant / genetics*,  physiopathology
Reactive Oxygen Species / metabolism
Retina / pathology
Sequence Deletion
Young Adult
Grant Support
GTB07001//Telethon; TCR07002//Telethon
Reg. No./Substance:
0/Reactive Oxygen Species; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/OPA1 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated ...
Next Document:  Dynamic variation in allele-specific gene expression of Paraoxonase-1 in murine and human tissues.