Macular dystrophies are an important group of diseases leading to loss of central vision and blindness. Recent genetic studies of a group of patients with autosomal dominant Stargardt-like macular dystrophies identified a 5-bp deletion in ELOVL4 gene. Its predicted protein has a high degree of homology to mammalian and yeast enzymes involved in the membrane-bound fatty acid chain elongation system. The human pathogenic deletion leads to a truncated protein with a net loss of 44 amino acids, including a di-lysine endoplasmic reticulum (ER) retention motif. The deletion can lead to perturbation of biosynthesis of very long chain fatty acids, resulting in their reduced synthesis in the ER and/or abnormal, ectopic synthesis outside the ER. Besides these two pathogenic mechanisms, there is also a possibility that the truncated ELOVL4 protein is toxic. To achieve our long-term goal of understanding pathophysiology of macular dystrophies and subsequently preventing vision loss, we propose the generation of Stgd3 knockin mice carrying human ELOVL4 deletion as well as Elovl4 knockout mice. These mice will be characterized by structural, functional, and biochemical studies of the retina, using microscopy, immunocytochemistry, electroretinography, as well as lipid and protein analysis. Our research will address the following specific aims: (i) understanding of the function of the ELOVL4 gene in physiology and pathology of the retina, and (ii) elucidation of the mechanism of disease for the STGD3 mutation.
| McMahon, Anne; Jackson, Shelley N; Woods, Amina S et al. (2007) A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32-C36 acyl phosphatidylcholines. FEBS Lett 581:5459-63 |
| McMahon, Anne; Butovich, Igor A; Mata, Nathan L et al. (2007) Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4. Mol Vis 13:258-72 |
