Molecular Biological Research for Retinitis Pigmentosa

视网膜色素变性是一组遗传性疾病，表现为双眼视力和视野进行性丧失，并伴有夜盲。这是导致日本成年人法律失明的第三大原因(12%)。由于RP的遗传性，有必要在基因水平上进行研究，以更好地了解RP的发病机制，以便我们能够设计出比目前更好或更有效的治疗方案。在本研究项目中，我们进行了RP的分子遗传学研究，特别是检测日本RP患者基因异常的研究。作为第一个项目，我们寻找日本常染色体显性遗传RP(ADRP)患者及其近缘病患者的视紫红质基因和外周蛋白/RDS基因突变。我们使用了在我们过去的研究项目(科学研究补助金，B-O354411)中建立的非放射定位SSCP方法来检测假定的突变。到目前为止，我们已经检测到视紫红质基因第347密码子(Pro347Leu)的点突变。我们还鉴定了外周蛋白/RDS基因的5个不同的突变，它们分别是Asn244Lys、Asn244His、Tyr184Ser、Arg172Trp和Val200Glu。基因-表型相关性研究表明Asn244Lys引起视锥细胞营养不良，Asn244His、Tyr184Ser和Val200Glu引起视锥细胞细胞营养不良，Arg172Trp导致黄斑营养不良。结果表明，该致病基因与19q染色体上的基因座(D19S180，Zmax=5.110)存在正连锁。进一步的分子遗传学研究将阐明该基因座的候选基因。

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.