ヒト先天性白内症モデルマウス、RCT,の原因遺伝子と修飾遺伝子の単離と機能解析

人类先天性白化病模型小鼠致病基因和修饰基因的分离和功能分析，RCT

• 批准号: 14540570
• 负责人: MAEDA Yukiko
• 金额: $ 2.3万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14540570/
• 关键词: congenital cataract; cataract mouse; rct gene; modifier gene; disease model mouse; congenital cataract; cataract mouse; desease model mouse; rct gene; mrct gene; modifier genes; modifier gene; cataract gene; disease model mouse

RCT is a new congenital cataract mouse associated with microphthalmia, which has been found in SJL/J strain as a spontaneous recessive mutant Small but clear histological change in epithelial cells of the lens was observed at 2 days after birth. The opacity of the lens could be observed visually at 3 to 3.5 months of the age. This cataract is regulated by two recessive genes, rct and mrct (a modifier of rct), on Chromosome (Chr.) 4 and 5, respectively. The rct gene is essential for the onset of the cataract (Maeda, YY. et. al., Mann. Genome, 2001). To clone the rct gene, we generated 2,161 individuals of F_2 progeny between RCT and MSM/Ms which is an inbred strain established from Japanese wild mouse Mus musculus molossinus, and carried out fine mapping for the rct locus. As the result, the locus was found to be present on a DNA fragment of approximately 1.09 Mbps. Then, we generated a congenic strain (N_<13>), in which the DNA fragment including rct locus was substituted with the corresponding DNA of MSM/Ms mice, and found that mice in the strain have normal lens. Next, we performed BAC-transgenic rescue using several BAC clones, some of which can be expected to include the rct locus. We obtained several lines of transgenic (Tg) mice and phenotype survey is now in progress.A new additional modifier locus, mrct2, was found on Chr.1. To examine the interaction between the mrct2 and mrct1 on Chr 5, we are now generating several congenic strains. Our preliminary results showed that mrct1 and mrct2 were located to be on 3 cM and 15 cM DNA fragments on corresponding chromosomes, respectively, and that the mrct1 showed relatively stronger effect than the mrct2. Both modifiers also showed a synergetic effect.

RCT是在SJL/J系小鼠中发现的一种先天性白内障伴小眼症小鼠，为自发性隐性突变。出生后2天，观察到透镜上皮细胞微小但清晰的组织学改变。透镜的不透明可在3至3.5月龄时目视观察到。这种白内障是由染色体上的两个隐性基因rct和mrct（rct的修饰基因）调控的。4和5所示。rct基因对于白内障的发作是必需的（Maeda，YY. et.例如，曼恩Genome，2001）。为了克隆rct基因，我们用日本小家鼠（Musmusculusmolossinus）的近交系（MSM/Ms）与RCT杂交产生了2,161个F_2代个体，并对rct基因进行了精细定位。结果，发现该基因座存在于约1.09Mbps的DNA片段上。然后，我们将<13>含有rct位点的DNA片段与MSM/Ms小鼠相应的DNA进行置换，得到了一个同源品系（N_），发现该品系小鼠具有正常的透镜。接下来，我们使用几个BAC克隆进行BAC转基因拯救，其中一些可以预期包括rct基因座。我们获得了几个品系的转基因（Tg）小鼠，目前正在进行表型调查，在Chr. 1上发现了一个新的额外修饰位点mrct 2。为了研究Chr 5上mrct 2和mrct 1之间的相互作用，我们现在正在产生几个同源菌株。我们的初步结果表明，mrct 1和mrct 2分别位于相应染色体上3cM和15 cM的DNA片段上，并且mrct 1比mrct 2表现出相对更强的作用。两种改性剂也表现出协同效应。

项目成果

Mutations in a new scaffold protein Sans cause deafness in Jackson shaker mice

• DOI: 10.1093/hmg/ddg042
• 发表时间: 2003-03-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Kikkawa, Y;Shitara, H;Yonekawa, H
• 通讯作者: Yonekawa, H

モデル動物の作製と維持 第1章第2節 感覚器、眼 (森脇和郎, 山村研一, 米川博通, 編)、

模型动物的制作和维护第一章第二节感觉器官、眼睛（森胁一郎、山村健一、米川弘道等编）

• 发表时间: 2004
• 作者: 前田幸子

Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin.

• DOI: 10.1093/hmg/ddg051
• 发表时间: 2003-03
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: D. Weil;A. El-Amraoui;S. Masmoudi;M. Mustapha;Y. Kikkawa;Sophie Lainé;S. Delmaghani;A. Adato

A Small Deletion Hotspot in the Type II Keratin Gene mK6irs1/Krt2-6g on Mouse Chromosome 15, A Candidate for Causing the Wavy Hair of the Caracul (Ca) Mutation

小鼠 15 号染色体上 II 型角蛋白基因 mK6irs1/Krt2-6g 的小缺失热点，是导致 Caracul (Ca) 突变的卷发的候选者

• 发表时间: 2003
• 期刊: Genetics 165
• 作者: Kikkawa;Y.;et al.
• 通讯作者: et al.

感覚器、眼、"モデル動物の作製と維持"(森脇和郎, 山村研一, 米川博通 編)

感觉器官、眼睛《模型动物的制作与维持》（森胁和夫、山村健一、米川弘道编）

• 发表时间: 2004
• 作者: 前田 幸子