A MOLECULAR GENETIC STUDY OF RETINAL DEGENERATION

临床和分子遗传学研究进行了阐明不同组视网膜变性的病理机制。以下是对研究结果的总结。为了研究促生存剂对光致大鼠和小鼠视网膜变性的拯救作用，我们在实验动物的玻璃体内注射midkine、bFGF或其他神经营养药物，对视网膜病变的延缓和视觉功能的维持有显著的预防作用。光感受器的恢复与光感受器内段核糖体的破坏程度降低有关。以视网膜变性为表现的各种疾病的分子遗传学研究揭示了致病基因的突变。值得注意的是，在4个日本诺里病家族中发现了诺里病基因的新突变，2个家族在第2外显子起始密码子处出现无义突变，1个家族在第3外显子95密码子处出现错义突变，1个家族可能出现了基因的串联重复，由此得出该疾病是由致病基因的异质突变群引起的。此外，在一例增殖性糖尿病视网膜病变患者中发现线粒体基因3243位核苷酸突变，该患者表现为孤立性糖尿病，无其他神经系统疾病。在Oguchi病中，视紫红质基因是正常的，但偶然发现了一个新的多态性。

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.