Yamagishi S, Nakamura K, Inoue H, Takeuchi M
Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Med Hypotheses. 2005;64(6):1202-4. doi: 10.1016/j.mehy.2005.01.017.
Age-related macular degeneration (ARMD) is the most common cause of acquired blindness among the people of occupational age. Although the pathogenesis of ARMD is not fully understood, several studies suggest a possible contribution of a genetic factor in the development and progression of ARMD. Pigment epithelium-derived factor (PEDF), a glycoprotein that belongs to the superfamily of serine protease inhibitors, was first purified from the conditioned media of human retinal pigment epithelial cells as a factor with potent neuronal differentiating activity in human retinoblastoma cells. Recently, PEDF has been shown to be a highly effective inhibitor of angiogenesis in cell culture and animal models. In addition, PEDF has been found in the vitreous, and its levels were decreased in angiogenic eye diseases, thus suggesting that a loss of PEDF in the eye is functionally important in the pathogenesis of ARMD. A functional amino acid change, a methionine to threonine polymorphism (Met72Thr polymorphism) at codon 72 in exon 3 (T/C polymorphism) of the PEDF gene, that results in the formation of BsstSI restriction site, has recently been identified. Since it is well known that a single nucleotide polymorphism and resultant amino acid change often alters the activity or expression level of the target protein, we would like to propose here a novel hypothesis that the Met72Thr polymorphism (T/C polymorphism) of PEDF gene may be a genetic marker for ARMD. Are genotype and allele frequencies of the Met72Thr polymorphism (T/C polymorphism) different between the patients with or without ARMD? Is this polymorphism associated with disease severity and progression? If the answer is yes, does this Met72Thr polymorphism regulate the vitreous levels of PEDF? These clinical studies could provide us with information whether this genetic variant of the PEDF gene could present an attractive candidate susceptibility gene for ARMD.
年龄相关性黄斑变性（ARMD）是职业年龄人群后天性失明的最常见原因。尽管ARMD的发病机制尚未完全明确，但多项研究表明遗传因素可能在ARMD的发生和发展中起作用。色素上皮衍生因子（PEDF）是一种糖蛋白，属于丝氨酸蛋白酶抑制剂超家族，最初是从人视网膜色素上皮细胞的条件培养基中纯化出来的，作为一种在人视网膜母细胞瘤细胞中具有强大神经元分化活性的因子。最近，PEDF在细胞培养和动物模型中已被证明是一种高效的血管生成抑制剂。此外，在玻璃体液中发现了PEDF，并且其水平在血管生成性眼病中降低，因此提示眼部PEDF的缺失在ARMD发病机制中具有重要功能。最近，在PEDF基因外显子3（T/C多态性）的第72密码子处发现了一种功能性氨基酸变化，即甲硫氨酸到苏氨酸的多态性（Met72Thr多态性），该变化导致形成BsstSI限制性位点。由于众所周知，单核苷酸多态性及由此产生的氨基酸变化常常会改变靶蛋白的活性或表达水平，我们在此提出一个新的假说，即PEDF基因的Met72Thr多态性（T/C多态性）可能是ARMD的一个遗传标记。患有或未患有ARMD的患者之间，Met72Thr多态性（T/C多态性）的基因型和等位基因频率是否不同？这种多态性是否与疾病严重程度和进展相关？如果答案是肯定的，那么这种Met72Thr多态性是否会调节玻璃体液中PEDF的水平？这些临床研究可以为我们提供信息，即PEDF基因的这种遗传变异是否可能是ARMD一个有吸引力的候选易感基因。
