Molecular Biological Research for Retinitis Pigmentosa

色素性视网膜炎（RP）是一组遗传性疾病，表现为双侧视力和视野进行性丧失和夜盲症。这是日本成年人法定失明的第三大常见原因（12%）。由于其遗传性质，需要从基因水平上进行研究，以更好地了解RP的发病机制，从而设计出比现有治疗方法更好或更有效的治疗方法。在本研究项目中，我们开展了RP的分子遗传学研究，特别是对日本RP患者基因异常的检测研究。作为第一个项目，我们在常染色体显性RP （adRP）和相关疾病的日本患者中寻找视紫红质基因和外周蛋白/RDS基因的突变。我们采用了在我们过去的研究项目（科学研究资助项目，B-O354411）中建立的非放射性同位素SSCP方法来检测假定的突变。到目前为止，我们已经在视紫红质基因的密码子347 （Pro347Leu）上检测到一个点突变。我们还鉴定了5种不同的外周蛋白/RDS基因突变，它们分别是Asn244Lys、Asn244His、Tyr184Ser、Arg172Trp和Val200Glu。基因型-表型相关研究发现，Asn244Lys导致杆状锥体营养不良，Asn244His、Tyr184Ser和Val200Glu导致杆状锥体营养不良，Arg172Trp导致黄斑营养不良。作为第二部分，我们使用几个遗传标记对adRP大家族进行了连锁分析。结果表明，该疾病基因与染色体19q位点呈正连锁（D19S180, Zmax=5.110）。进一步的分子遗传学研究将阐明该位点的候选基因。

Retinitis Pigmentosa (RP) is a group of hereditary disorders which show bilateral progressive loss of visual acuity and visual field, and night blindness. This is the third most frequent cause (12%) of legal blindness among adult Japanese population. Because of its hereditary nature, researches at the level of genes should be necessary to obtain better understandings of the mechanism of pathogenesis of RP,so that we can specifically design better or more effective modalities of treatment than what we have now.In this study project, we have performed molecular genetic researches for RP,especially studies for detecting gene abnormalities in Japanese patients with RP.As the first project, we searched for mutations within the rhodopsin gene and the peripherin/RDS gene in Japanese patients with autosomal dominant RP (adRP) and allied deseases. We employed nonradiosotopic SSCP method that had been established in our past research project (Grant-in-Aid for Scientific Research, B-O354411) to detect putative mutations. To date, we have detected a point mutation in codon 347 (Pro347Leu) in the rhodopsin gene. We also have identified 5 different mutations in the peripherin/RDS gene, and they were Asn244Lys, Asn244His, Tyr184Ser, Arg172Trp, and Val200Glu, respectively. Studies for genotype-phenotype correlation have revealed that Asn244Lys causes rod-cone dystrophy, while Asn244His, Tyr184Ser, and Val200Glu cause cone-rod dystrophy, and Arg172Trp is responsible for macular dystrophy.As the second part, we have perfoumed linkage analysis for a large family with adRP using several genetic markers. As a result, a positive linkage was obtained between the desease gene and the locus on chromosome 19q (D19S180, Zmax=5.110). Further molecular genetic study will clarify a candidate gene for this locus.