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.

本研究的目的是检查遗传性视网膜疾病，特别是视锥（杆）营养不良的致病基因，并比较患者的基因型和表型。我们对38个视锥（杆）营养不良家系的CRX、RETGC1、peripherin/RDS、GUCA1A、HRG4、ABCA4和RPGR基因进行了分析，发现2个家系中存在CRX基因突变，3个家系中发现了3个RETGC1基因突变，以及家族中的外周蛋白/RDS基因突变。 CRX 基因突变和 2 个 RETGC1 基因突变已在白种人群体中报道，表明该密码子是国际上常染色体显性视杆细胞营养不良的焦点。我们在 RETGC1 基因中发现了一个新的复杂突变 Ile9l5Thr+Gly9l7Arg。在这次筛查中，在10个常染色体显性家族中有4个发现了致病基因突变，这表明在日本人群中可以以相对较高的频率确定视锥（杆）营养不良的致病突变。同一基因中的相同突变在不同种族中导致总体相似的临床表型，然而，患者之间的严重程度不同，这表明除了已识别的突变之外，还有一些环境或遗传因素影响了严重程度。除了视锥（杆）营养不良之外，我们分析了许多眼底白斑病例的基因型-表型相关性。我们发现一些不完全先天性静止性夜盲症病例与进行性视网膜和视神经萎缩有关。一个患有增强型 s 锥综合征的病例与视网膜下新生血管形成有关。我们发现了一例由 CRX 基因从头突变引起的莱伯先天性黑蒙病例。

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）。