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Analysis of infertility in systemic carnitine deficient mouse (JVS mouse)

全身性肉碱缺乏小鼠（JVS小鼠）不育分析

基本信息

批准号：
10671477
负责人：
MURAKAMI Takashi
金额：
$ 1.28万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Juvenile Visceral Steatosis (JVS) mouse, which we reported in 1991, serves as an animal model of primary carnitine deficiency. Because this mouse is suffered from severe male infertility, we analyzed the cause and mechanism. The summary of the results is as follows ;1. Analysis of candidate geneAs a human OCTN2 gene encoding a sodium-dependent carnitine cotranspoter was isolated, we isolated the mouse octn2 gene and screened for its mutation in the JVS mouse. DNA sequencing analysis disclosed a missense mutation from CTG (Leu) to CGG (Arg) at codon 352 located within the sixth transmembrane domain of octn2. This amino acid replacement possibly causes the conformational change of the protein that leads to dysfunction of the gene product.2. Analysis of epididymisAt 8-9 weeks of age, the epididymis was deformed, and its weight was significantly increased. Histologically, the duct of proximal epididymis was dilated due to the accumulation of unusually high level of spermatozoa. Spermatozoa ware extravasated from the epididymal duct into the stroma. In contrast, the duct of the distal epididymis was constricted and contained no spermatozoa. Thus, the epididymal disorder causes obstructive azoospermia, leading to infertility.3. Discovery of camitine transport inhibitorThe site of action of 3-(2,2,2-trimethylhydrozinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. As a result, it was indicated that the principal site of action of THP is the carnitine-transport carrier in kidney but not the carrier in heart.

幼年内脏脂肪变性（JVS）小鼠，我们在1991年报道，作为一种动物模型的原发性肉毒碱缺乏症。由于该小鼠患有严重的雄性不育症，我们分析了原因和机制。结果总结如下：1.候选基因的分析由于分离了编码钠依赖性肉毒碱共转运蛋白的人octn 2基因，我们分离了小鼠octn 2基因并在JVS小鼠中筛选其突变。DNA测序分析揭示了位于octn 2的第六跨膜结构域内的密码子352处从CTG（Leu）到CGG（Arg）的错义突变。这种氨基酸替换可能引起蛋白质构象的变化，导致基因产物功能障碍.附睾分析8-9周龄时，附睾畸形，重量明显增加。组织学上，由于异常高水平的精子聚集，附睾近端导管扩张。精子从附睾管外渗到间质中。相反，附睾远端的导管收缩，不含精子。因此，附睾疾病引起梗阻性无精子症，导致不育。3.卡米汀转运体的发现研究了一种新的心肌保护剂3-（2，2，2-三甲基肼）丙酸盐（THP）在小鼠和大鼠体内的作用部位。结果表明，THP的主要作用部位是肾脏中的肉毒碱转运载体，而不是心脏中的载体。