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

我们在1991年报道的幼年型内脏脂肪变性（JVS）小鼠作为原发性肉毒碱缺乏的动物模型。由于这只小鼠患有严重的雄性不育，我们分析了原因和机制。结果总结如下：1。候选基因分析在分离到人OCTN2基因后，我们分离了小鼠OCTN2基因，并在JVS小鼠中筛选其突变。DNA测序分析发现，位于octn2第6跨膜结构域密码子352处的CTG （Leu）错义突变为CGG （Arg）。这种氨基酸的替换可能引起蛋白质的构象改变，从而导致基因产物的功能障碍。附睾分析8 ~ 9周龄时，附睾变形，重量明显增加。组织学上，由于异常高水平精子的积累，近端附睾管扩张。精子从附睾管外渗到间质中。相比之下，附睾远端管狭窄，不含精子。因此，附睾疾病引起阻塞性无精子症，导致不孕症。研究了一种新型心脏保护剂3-（2,2,2-三甲基氢锌）丙酸酯（THP）在小鼠和大鼠体内的作用位点。结果表明，THP的主要作用部位是肾脏的肉毒碱转运载体，而不是心脏的转运载体。

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.