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Rainald G Schmidt-Kastner, Tyler Seidman, Gabriel Quinones-Medina, Birgit Lorenz, Markus N Preising; Links between the endoplasmatic reticulum protein WFS1/Wolframin and mitochondrial proteins defined in silico may explain optic atrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6230.
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© ARVO (1962-2015); The Authors (2016-present)
Wolfram syndrome 1 (WFS1, MIM 222300) is caused by recessive mutations of WFS1 (wolframin) that lead to optic atrophy, diabetes mellitus, diabetes insipidus and hearing loss. WFS1 is expressed in the human retina (Schmidt-Kastner et al., Exp. Eye Res. 2009). WFS1 is localized to the endoplasmic reticulum (ER) and associated with ER stress. WFS2 (MIM 604928) is caused by mutations of CISD2, localized to ER and mitochondria. Since optic atrophy is predominantly caused by mutations related to mitochondrial function, we hypothesized that WFS1 in the ER must be closely associated with mitochondrial proteins. In silico studies of protein-protein interactions (PPIs) were used to identify putative mitochondrial partner proteins.
GeneMANIA was used to retrieve PPIs of WFS1 and CISD2 (150 interactions; human, mouse and rat data combined). PPIs were intersected with a database of mitochondrial proteins (MitoCarta). Nuclear-encoded mitochondrial genes known to cause optic atrophy were collected from NEIBank, OMIM and Mitophenome (n=31); PPIs (n=20 interactions; human) were generated and annotated for mitochondrial functions (MitoCarta; DAVID Bioinformatics).
PPIs of WFS1 contained n=15 mitochondrial proteins, including MRPS31, a mitochondrial ribosome protein previously identified as auto-antigen IMOGEN 38 in type 1 diabetes mellitus. WFS1 and MRPS31 interact with EIF6 (BioGRID) that controls ribosome activity. PPIs for CISD2 had enriched links to mitochondrial proteins (n=20; chi-square p=0.03) including MRPL43 and MRPL51. The only PPI shared by WFS1 and CISD2 was with Rhot2 (MIRO-2), an axonal transport protein for mitochondria. PPIs for mitochondrial genes causative in optic atrophy (n=8) contained links to the mitochondrial ribosome (DAVID, p<0.05 Bonferroni). Reverse searches in PPIs of mitochondrial ribosome proteins (n=77) also lead to proteins related to optic atrophy.
WFS1 and CISD2 were tentativey linked to proteins of the mitochondrial ribosome via PPI datasets. In addition, PPIs of nuclear encoded mitochondrial genes causing optic atrophy contained links to the mitochondrial ribosome. ER synthesis of nuclear encoded mitochondrial ribosome proteins and transport from ER into mitochondria are suggested as targets for experimental and translational studies on optic atrophy in WFS1.
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