Title : Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in
ELOVL4
Abstract :
- ELOVL4 ( elongation of very long very long chain fatty acids 4) is a member of the ELO family of proteins involved in the biosynthesis of very long chain fatty acids
- Protein truncation mutations in ELOVL4 have been identified in patients with autosomal dominant Stargardt-like macular degeneration
- To determine whether a dominant negative mechanism is responsible for the autosomal dominant inheritance pattern of this disease, we studied the subcellular localization and interaction of wild type and mutant ELOVL4 in COS-7 and HEK 293T cultured cells by immunofluorescence and co-immunoprecipitation
- Wild type ELOVL4 containing an endoplasmic reticulum retention sequence was localized to the endoplasmic reticulum as expected
- In contrast, disease-associated C-terminal truncation ELOVL4 mutants accumulated as large inclusions exhibiting aggresome-like characteristics in a juxtanuclear position within COS-7 cells
- When the wild type and mutant proteins were co-expressed incultured cells, wild type ELOVL4 co-purified with mutant ELOVL4 on an immunoaffinity column and co-localized with the mutant protein in aggresome-like inclusions adjacent to the nucleus
- These results indicate that wild type and mutant ELOVL4 form a complex that exhibits an abnormal subcellular localization found for individually expressed mutant ELOVL4
- From these studies, we conclude that disease-linked C-terminal truncation mutants of ELOVL4 exert a dominant negative effect on wild type ELOVL4 , altering its subcellular localization
- This dominant negative mechanism contributes to the autosomal dominant inheritance of Stargardt-like macular dystrophy
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