Barabas Peter, Gorusupudi Aruna, Bernstein Paul S, Krizaj David
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Institute, University of Utah School of Medicine, 84132, Salt Lake City, UT, USA.
Adv Exp Med Biol. 2016;854:137-43. doi: 10.1007/978-3-319-17121-0_19.
Stargardt type 3 macular degeneration is dependent on a dominant defect in a single gene, ELOVL4 (elongase of very long chain fatty acids 4). The encoded enzyme, ELOVL4, is required for the synthesis of very long chain polyunsaturated fatty acids (VLC-PUFAs), a rare class of > C24 lipids. In vitro expression studies suggest that mutated ELOVL4(STGD3) proteins fold improperly, resulting in ER stress and formation of cytosolic aggresomes of wild type and mutant ELOVL4. Although a number of mouse models have been developed to determine whether photoreceptor cell loss in STGD3 results from depletion of VLC-PUFAs, aggresome-dependent cell stress or a combination of these two factors, none of these models adequately recapitulates the disease phenotype in humans. Thus, the precise molecular mechanism by which ELOVL4 mutation causes photoreceptor degeneration in mice and in human patients remains to be characterized. This mini review compares and evaluates current STGD3 mouse models and determines what conclusions can be drawn from past work.
3型斯塔加特黄斑变性取决于单个基因ELOVL4（极长链脂肪酸延长酶4）中的显性缺陷。编码的酶ELOVL4是合成极长链多不饱和脂肪酸（VLC-PUFAs，一类罕见的>C24脂质）所必需的。体外表达研究表明，突变的ELOVL4（STGD3）蛋白折叠不当，导致内质网应激以及野生型和突变型ELOVL4的胞质聚集体形成。尽管已经开发了许多小鼠模型来确定STGD3中光感受器细胞丢失是由于VLC-PUFAs耗尽、聚集体依赖性细胞应激还是这两种因素的组合，但这些模型均未充分重现人类疾病表型。因此，ELOVL4突变导致小鼠和人类患者光感受器变性的确切分子机制仍有待阐明。本综述比较并评估了当前的STGD3小鼠模型，并确定了可以从过去的研究中得出哪些结论。
