Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Sreemathi Logan, Martin Paul Agbaga, Michael D. Chan, Nabila Kabir, Nawajes Mandal, Richard S. Brush, Robert E. Anderson

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4),whereas recessivemutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-relatedmacular degenerationmay be a contributing factor to their retinal pathology.

Original languageEnglish (US)
Pages (from-to)5446-5451
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number14
DOIs
StatePublished - Apr 2 2013

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Macular Degeneration
Fatty Acids
Poisons
Mutant Proteins
Microsomes
Unsaturated Fatty Acids
Endoplasmic Reticulum
Organelles
Proteins
Pathology
Skin
Mutation
Brain
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. / Logan, Sreemathi; Agbaga, Martin Paul; Chan, Michael D.; Kabir, Nabila; Mandal, Nawajes; Brush, Richard S.; Anderson, Robert E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 14, 02.04.2013, p. 5446-5451.

Research output: Contribution to journalArticle

Logan, Sreemathi ; Agbaga, Martin Paul ; Chan, Michael D. ; Kabir, Nabila ; Mandal, Nawajes ; Brush, Richard S. ; Anderson, Robert E. / Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 14. pp. 5446-5451.
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