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Identification and characterization of mutations in the Drosophila mitochondrial translation elongation factor iconoclast

Mitochondrial disorders resulting from defects in oxidative phosphorylation are the most common form of inherited metabolic disease. Mutations in the human mitochondrial translation elongation factor GFM1 have recently been shown to cause the lethal pediatric disorder Combined Oxidative Phosphorylation Deficiency Syndrome (COXPD1). Children harboring mutations in GFM1 exhibit severe developmental, metabolic and neurological abnormalities. This work describes the identification and extensive characterization of the first known mutations in iconoclast (ico), the Drosophila orthologue of GFM1. Expression of human GFM1 can rescue ico null mutants, demonstrating functional conservation between the human and fly proteins. While point mutations in ico result in developmental defects and death during embryogenesis, animals null for ico survive until the second or third instar larval stage. These results indicate that in addition to loss-of-function consequences, point mutations in ico appear to produce toxic proteins with antimorphic or neomorphic effects. Consistent with this hypothesis, transgenic expression of a mutant ICO protein is lethal when expressed during development and inhibits growth when expressed in wing discs. In addition, animals with a single copy of an ico point mutation are more sensitive to acute hyperthermic or hypoxic stress. Removal of the positively-charged tail of the protein abolishes the toxic effects of mutant ICO, demonstrating that this domain is necessary for the harmful gain-of-function phenotypes observed in ico point mutants. / Further, expression of GFP-tagged constructs indicates that the C-terminal tail enhances ectopic nuclear localization of mutant ICO, suggesting that mislocalization of the protein may play a role in the antimorphic effects of mutant ICO. Taken together, these results illustrate that in addition to loss-of-function effects, gain-of-function effects can contribute significantly to the pathology caused by mutation in mitochondrial translation elongation factors. / by Catherine F. Trivigno. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

Identiferoai:union.ndltd.org:fau.edu/oai:fau.digital.flvc.org:fau_3535
ContributorsTrivigno, Catherine F., Charles E. Schmidt College of Science, Department of Biological Sciences
PublisherFlorida Atlantic University
Source SetsFlorida Atlantic University
LanguageEnglish
Detected LanguageEnglish
TypeText, Electronic Thesis or Dissertation
Formatxii, 84 p. : ill. (some col.), electronic
Rightshttp://rightsstatements.org/vocab/InC/1.0/

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