Department of Ophthalmology, University of California San Diego, #206, Jacobs Retina Center, La Jolla, CA, USA.
Prog Retin Eye Res. 2010 May;29(3):191-207. doi: 10.1016/j.preteyeres.2010.01.001. Epub 2010 Jan 21.
Stargardt-like macular degeneration (STGD3) is an early onset, autosomal dominant macular degeneration. STGD3 is characterized by a progressive pathology, the loss of central vision, atrophy of the retinal pigment epithelium, and accumulation of lipofuscin, clinical features that are also characteristic of age-related macular degeneration. The onset of clinical symptoms in STGD3, however, is typically observed within the second or third decade of life (i.e., starting in the teenage years). The clinical profile at any given age among STGD3 patients can be variable suggesting that, although STGD3 is a single gene defect, other genetic or environmental factors may play a role in moderating the final disease phenotype. Genetic studies localized the STGD3 disease locus to a small region on the short arm of human chromosome 6, and application of a positional candidate gene approach identified protein truncating mutations in the elongation of very long chain fatty acids-4 gene (ELOVL4) in patients with this disease. The ELOVL4 gene encodes a protein homologous to the ELO group of proteins that participate in fatty acid elongation in yeast. Pathogenic mutations found in the ELOVL4 gene result in altered trafficking of the protein and behave with a dominant negative effect. Mice carrying an Elovl4 mutation developed photoreceptor degeneration and depletion of very long chain fatty acids (VLCFA). ELOVL4 protein participates in the synthesis of fatty acids with chain length longer than 26 carbons. Studies on ELOVL4 indicate that VLCFA may be necessary for normal function of the retina, and the defective protein trafficking and/or altered VLCFA elongation underlies the pathology associated with STGD3. Determining the role of VLCFA in the retina and discerning the implications of abnormal trafficking of mutant ELOVL4 and depleted VLCFA content in the pathology of STGD3 will provide valuable insight in understanding the retinal structure, function, and pathology underlying STGD3 and may lead to a better understanding of the process of macular disease in general.
斯塔加特型黄斑营养不良(STGD3)是一种早发性常染色体显性黄斑营养不良。STGD3 的特征是进行性病变、中心视力丧失、视网膜色素上皮萎缩和脂褐素积累,这些临床特征也是年龄相关性黄斑变性的特征。然而,STGD3 的临床症状发作通常发生在第二或第三个十年(即青少年时期)。STGD3 患者在任何特定年龄的临床特征可能存在差异,这表明尽管 STGD3 是一种单一基因缺陷,但其他遗传或环境因素可能在调节最终疾病表型方面发挥作用。遗传研究将 STGD3 疾病基因座定位到人类 6 号染色体短臂的一个小区域,应用定位候选基因方法在患有这种疾病的患者中鉴定出延长非常长链脂肪酸 4 基因(ELOVL4)的蛋白截断突变。ELOVL4 基因编码一种与 ELO 蛋白家族同源的蛋白,该蛋白参与酵母中脂肪酸的延长。在 ELOVL4 基因中发现的致病性突变导致蛋白的运输改变,并表现出显性负效应。携带 Elovl4 突变的小鼠发生光感受器变性和非常长链脂肪酸(VLCFA)耗竭。ELOVL4 蛋白参与合成链长超过 26 个碳原子的脂肪酸。对 ELOVL4 的研究表明,VLCFA 可能是视网膜正常功能所必需的,而缺陷的蛋白运输和/或改变的 VLCFA 延长是与 STGD3 相关的病理学的基础。确定 VLCFA 在视网膜中的作用,并了解突变 ELOVL4 的异常运输和耗尽的 VLCFA 含量在 STGD3 病理学中的意义,将为理解 STGD3 下的视网膜结构、功能和病理学提供有价值的见解,并可能导致更好地理解黄斑疾病的一般过程。