A MOLECULAR GENETIC STUDY OF RETINAL DEGENERATION

临床和分子遗传学研究被用来阐明一组不同的视网膜变性的发病机制。为研究促生剂对大鼠和小鼠视网膜光损伤的修复作用，实验动物经玻璃体内注射Midkine、bFGF或其他神经营养剂，对视网膜病变的延缓和视功能的维持有显著的预防作用。光感受器的挽救与减少光感受器内节段核糖体的破坏有关。对以视网膜变性为表现的各种疾病的分子遗传学研究显示，致病基因发生了突变。值得注意的是，在4个日本家系中发现了Norrie病基因的新突变，其中2个家系在外显子2的起始密码子上出现无义突变，1个家系在外显子3的密码子95处发生错义突变，1个家系可能存在该基因的串联重复，从而得出结论：该病是由致病基因的一组异源突变引起的。此外，在一例增殖性糖尿病视网膜病变患者中发现了线粒体基因3243位核苷酸的突变，该患者表现为孤立的糖尿病，没有任何其他神经疾病。视紫红质基因在Oguchi病中是正常的，但偶然发现了一种新的基因多态性。

Clinical and molecular genetic studies were carried out to elucidate the pathomechanism of a diverse group of retinal degeneration. The followings are the summary of research results.To study rescue effects of survival-promoting agents on light-induced retinal degeneration in rats and mice, the experimental animals were pretreated with intravitreous injection of midkine, bFGF or other neurotrophic agents, which showed a remarkable prevention of delay of retinal pathologies and visual functional maintenance. The rescue of photoreceptors was associated with reduced disorganization of photoreceptor inner segment ribosomes.Molecular genetic studies of various diseases presenting with retinal degeneration revealed mutations in disease-causing genes. Noticeably, novel mutations were found in Norrie disease gene in four Japanese families with the disease, two families showed nonsense mutation at the initiation codon of the exon 2, one family had missense mutation at the codon 95 of exon 3, and one family illustrated probable tandem duplication of the gene, concluding that the disease is caused by a heterogenous group of mutations in the disease-causing gene. Also, a mutation at nucleotide position 3243 of mitochondrial gene was found in a patient with proliferative diabetic retinopathy, who showed isolated diabetes mellitus without any other neurologic disease. Rhodopsin gene was normal in Oguchi disease, but incidentally a new polymorphism was observed in the gene.