Identification of causative gene mutation and analysis of genotype-phenotype correlation in Japanese cone(-rod) dystrophy

日本视锥（杆）营养不良症致病基因突变鉴定及基因型-表型相关性分析

• 批准号: 14370556
• 负责人: NAKAMURA Makoto
• 金额: $ 2.5万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370556/
• 关键词: genetic retinal diseases; molecular genetics; cone dystrop; cone-rod dystrophy; CRX gene; RFTGC1 gene; fundus albipunctatus; incomplete congenital stationary night blindness; 遺伝子変異; 不全型先天停止性夜盲; RETGCI遺伝子

The purpose of this study is to examine the causative genes of genetic retinal diseases, especially of cone (-rod) dystrophy, and to compare the genotype and phenotype in the patients. We analyzed CRX, RETGC1,peripherin/RDS, GUCA1A, HRG4, ABCA4,and RPGR genes in 38 families with cone (-rod) dystrophy, and found a CRX gene mutation in 2 families,3 RETGC1 gene mutations in 3 families, and a peripherin/RDS gene mutation in a family. The CRX gene mutation and 2 of the RETGC1 gene mutations had been reported in Caucasian population indicating that the codons are focuses for autosomal dominant cone (-rod) dystrophy internationally. We found a novel complex mutation, Ile9l5Thr+Gly9l7Arg, in the RETGC1 gene. In this screening the causative gene mutations were found in 4 out of 10 autosomal dominant families indicating that the causative mutation of cone (-rod) dystrophy can be determined at relatively high frequency in Japanese population. The same mutations in the same gene caused an overall similar clinical phenotype in different races, however, the severity differed among the patients indicating some environmental, or genetic factors other than the identified mutations effected the severity.Besides cone (-rod) dystrophy, we analyzed the genotype-phenotype correlation in many cases with fundus albipunctatus. We found some cases with incomplete congenital stationary night blindness were associated with progressive retinal and optic atrophy. A case with enhanced s-cone syndrome was associated with subretinal neovascularization. We found a case with Leber congenital amaurosis caused by a de novo CRX gene mutation.

这项研究的目的是检查遗传性视网膜疾病的致病基因，尤其是锥体（-ROD）营养不良的原因，并比较患者的基因型和表型。我们分析了38个患有锥锥（-rod）营养不良的家族中CRX，RETGC1，外围蛋白/RDS，GUCA1A，HRG4，ABCA4和RPGR基因，并在2个家族中发现了CRX基因突变，3个retGC1基因突变中的3个家族中的3个家族中的3个家庭，以及一个家族rds Gene基因突变。在高加索人群中已经报道了CRX基因突变和2个RETGC1基因突变，表明这些密码子集中在国际上是常染色体显性锥（-ROD）营养不良。我们在RetGC1基因中发现了一个新型的复合物突变，即ILE9L5THR+GLY9L7ARG。在此筛查中，在10个常染色体显性遗传中发现了病因突变，表明可以在日本人群中以相对较高的频率确定锥体（-ROD）营养不良的致病突变。同一基因中的相同突变引起了不同种族的总体相似临床表型，但是，除了鉴定出的突变外，表明某些环境或遗传因素的患者之间的严重程度有所不同。Besides锥（-ROD）营养不良，我们分析了许多基因型 - 表型杂音的基因型 - 型号的基因型易位。我们发现有些病例患有先天性固定的夜间失明与进行性视网膜和视神经萎缩有关。 S-Cone综合征增强的病例与视网膜下新血管形成有关。我们发现了一个由从头crx基因突变引起的列伯先天性症状的病例。

项目成果

Hotta K, Nakamura M, Kondo M, Ito S, Terasaki H, Miyake Y, Hida T.: "Macular dystrophy in a Japanese family with fundus albipunctatus."Am J Ophthalmol.. 135. 917-919 (2003)

Hotta K、Nakamura M、Kondo M、Ito S、Terasaki H、Miyake Y、Hida T.：“患有眼底白斑的日本家庭中的黄斑营养不良。”Am J Ophamol.. 135. 917-919 (2003)

Piao CH, Kondo M, Nakamura M, Terasaki H, Miyake Y.: "Multifocal electroretinograms in X-linked retinoschisis."Invest Ophthalmol Vis Sci. 44. 4920-4930 (2003)

Piao CH、Kondo M、Nakamura M、Terasaki H、Miyake Y.：“X 连锁视网膜劈裂中的多焦点视网膜电图”。Invest Ophasemol Vis Sci。

Nakamura M, Skalet J, Miyake Y.: "RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy."Documenta Ophthaimologica.. 107. 3-11 (2003)

Nakamura M、Skalet J、Miyake Y.：“伴有或不伴有黄斑营养不良的眼底白斑的 RDH5 基因突变和视网膜电图。”Documenta Ophthaimologica.. 107. 3-11 (2003)

Nakamura M, et al.: "Macular dystrophy in a 9-year-old boy with fundus albipunctatus."Am J Ophthalmol.. 133. 278-280 (2002)

Nakamura M 等人：“患有眼底白斑的 9 岁男孩黄斑营养不良。”Am J Ophamol.. 133. 278-280 (2002)

Ito S, et al.: "Autosomal Dominant Cone-Rod Dystrophy with R838H and R838C Mutations in the GUCY2D Gene in Japanese Patients."Jpn J Ophthalmol.. (In press). (2004)

Ito S 等人：“日本患者中 GUCY2D 基因中存在 R838H 和 R838C 突变的常染色体显性锥杆营养不良。”Jpn J Ophamol..（正在印刷中）。