A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32–C36 acyl phosphatidylcholines

Abstract 

Stargardt disease-3 (STGD3) is a juvenile dominant macular degeneration caused by mutations in elongase of very long chain fatty acid-4. All identified mutations produce a truncated protein which lacks a motif for protein retention in endoplasmic reticulum, the site of fatty acid synthesis. In these studies of Stgd3-knockin mice carrying a human pathogenic mutation, we examined two potential pathogenic mechanisms: truncated protein-induced cellular stress and lipid product deficiency. Analysis of mutant retinas detected no cellular stress but demonstrated selective deficiency of C32–C36 acyl phosphatidylcholines. We conclude that this deficit leads to the human STGD3 pathology.

Abbreviations: AMD, age-related macular degeneration, DHA, docosahexaenoic acid, ELOVL4, elongase of very long chain fatty acid-4, ER, endoplasmic reticulum, MS, mass spectrometry, m/z, mass-to-charge ratio, N, nucleotide, PC, phosphatidylcholine, STGD3, Stargardt disease-3

Keywords: Stargardt disease-3, Retina, Very long chain fatty acid, Phosphatidylcholine, Unfolded-protein response, Mass spectrometry