Molecular Genetic Studies of Important Eye Diseases

本研究涉及重要眼病的分子遗传学分析。主要研究结果如下：1.诺里病诺里病是一种罕见的X染色体连锁疾病，表现为婴儿严重的玻璃体视网膜发育不良。我们以前在鹿儿岛县发现了两个家庭，在这项研究中，在东京和千叶又发现了两个家庭。对这四个家庭进行了诺里病基因突变检查。结果发现，鹿儿岛2个家系的第2外显子起始密码子发生突变，东京1个家系的第3外显子发生错义突变，千叶1个家系的基因发生严重重复. Sorsby眼底营养不良（SFD）是一种罕见的常染色体显性视网膜疾病，其特征是成人发病和进行性眼底营养不良，类似于年龄相关性黄斑变性。我们在鹿儿岛发现了两个SFD家庭，这是日本和亚洲的第一个。我们的两个家族被发现在内含子4/外显子5连接处有一个单核苷酸插入，预计会截短SFD蛋白。在白种人SFD患者中尚未报告这种类型的突变，这些患者均在SED基因编码区的C末端显示错义突变。同样有趣的是，我们的日本患者在疾病发作和疾病扩展方面与年龄相关性黄斑变性更为相似。先天性眼球震颤我们发现一个四代同堂的家族，其特征是先天性眼球震颤、角膜异常和中心凹发育不全。该疾病相关基因位于21号染色体上，对致病基因的搜索揭示了PAX 6配对结构域中的错义突变。值得注意的是，我们的患者在虹膜或葡萄膜组织中没有缺陷，尽管大多数PAX突变患者存在无虹膜。

This study dealt with molecular genetic analysis of important eye diseases. The main results are as follows.1. Norrie diseaseNorrie disease a rare X-linked disease that presents severe vitreoretinal dysplasia in infants. We had found previously two families in Kagoshima prefecture and during this study two additional families in Tokyo and Chiba. These four families were examined for mutations in the Norrie disease gene. As a result, two Kagoshima families had a mutation in the initiation codon of the exon 2, one family in Tokyo missense mutation in the exon 3, and one family in Chiba a gross duplication of the gene.2. Sorsby's fundus dystrophy (SFD SFD is a rare autosomal dominant retinal disease characterized by adult onset and progressive fundus dystrophy resembling age-related macular degeneration. We identified two families with SFD in Kagoshima, the first in Japan and Asia. Our two families were found to have a single nucleotide insertion in the intron4/exon 5 junction that predicted to truncate SFD protein. This type of mutation has not been reported in Caucasian SFD patients, who all showed missense mutations in the C-terminus of the coding region of the SED gene. It was also of interest that our Japanese patients were much more similar to age-related macular degeneration in its disease onset and extension of the disease.3. Congenital nystagmusWe identified a four-generation family featured by congenital nystagmus, corneal anomalies and foveal hypoplasia. The disease-associated gene was localized in chromosome 21, and a search for the causative gene has revealed a missense mutation in the paired domain of PAX6. It was remarkable that our patients had no defect in the iris or uveal tissue, although the majority of patients with PAX mutations present aniridia.