Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome
Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome
复制标题
DOI：
10.1007/s10545-007-0776-7
复制
发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Gibson, K. M.
中科院分区：
文献类型：
--
作者：
Hager, E. J.;Tse, H. M.;Gibson, K. M.
在本研究中，我们的目的是建立一个人类高IgD综合征（HIDS）和严重甲羟戊酸尿症（MA）的小鼠模型，与甲羟戊酸激酶缺乏症（MKD）相关的自身炎症性疾病。一个Mvk等位基因（Mvk（+/-））的缺失产生了肝脏Mvk酶活性显著降低的活小鼠;多次交配未能产生Mvk（-/-）小鼠。在Mvk（+/-）小鼠中，组织和血液中的胆固醇水平以及组织中的异戊二烯终产物（泛醌、多萜醇）均正常;相反，脾脏、心脏和肾脏中的甲羟戊酸浓度升高，但脑和肝脏中的甲羟戊酸浓度正常。虽然趋势是Mvk（+/-）血清中的伊加水平较高，但与Mvk（+/+）同窝出生的小鼠相比，IgD水平在年轻（< 15周）和年长（> 15周）小鼠中均显著增加（9-12倍）。与野生型同窝小鼠相比，Mvk（+/-）动物表现出血清TNF-α升高，但由于个体Mvk（+/-）小鼠之间的水平差异很大，平均值差异无统计学显著性。Mvk（+/-）小鼠代表了HIDS的第一个动物模型，并应证明可用于检查与这种疾病相关的病理生理学。
In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk(+/-)) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk(-/-) mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk(+/-) mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk(+/-) sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk(+/+) littermates, in both young (< 15 weeks) and older (> 15 weeks) mice. Mvk(+/-) animals manifested increased serum TNF-alpha as compared to wild-type littermates, but due to wide variation in levels between individual Mvk(+/-) mice the difference in means was not statistically significant. Mvk(+/-) mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.