Mice deficient for cytosolic thymidine kinase gene develop fatal kidney disease
Mice deficient for cytosolic thymidine kinase gene develop fatal kidney disease
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DOI：
10.1016/s1096-7192(02)00224-x
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发表时间：
2003-01-01
影响因子：
3.8
通讯作者：
Richardson, FC
中科院分区：
文献类型：
--
作者：
Dobrovolsky, VN;Bucci, T;Richardson, FC
胸苷激酶 (Tk) 基因编码参与嘧啶核苷酸挽救途径的胞质蛋白。功能性 Tk 基因对于培养的细胞来说并不是必需的，并且在人类或动物模型中尚未描述天然存在的 Tk 缺陷表型。为了确定Tk基因的生物学意义，我们通过小鼠胚胎干细胞同源重组创建了Tk(-/-)敲除(KO)小鼠。与野生型或 Tk 杂合 (HET) 小鼠相比，Tk KO 小鼠的寿命缩短。所有 Tk KO 小鼠均出现肾小球硬化，并在一岁前因肾衰竭而死亡。在 KO 动物的其他变化中，最一致的是舌下唾液腺从完全粘液分泌转变为以浆液分泌为主。 HET 父母可以以接近孟德尔遗传的频率产生 KO 小鼠。 KO动物中的其他观察结果包括血清胸苷水平升高、脾淋巴细胞克隆效率显着降低、次黄嘌呤鸟嘌呤磷酸核糖转移酶基因突变淋巴细胞频率增加以及脾脏淋巴结构的组织学改变。此外，KO动物偶尔表现出动脉炎症，再加上淋巴细胞和脾脏异常，表明免疫系统异常。 Tk KO 小鼠的改变表明嘧啶核苷酸挽救途径在体内是不可或缺的。 (C) 2002 年爱思唯尔科学（美国）。版权所有。
The thymidine kinase (Tk) gene codes for a cytosolic protein involved in the pyrimidine nucleotide salvage pathway. A functional Tk gene is not necessary for cells in culture, and a naturally occurring Tk deficient phenotype has not been described in humans or animal models. In order to determine the biological significance of the Tk gene, we created Tk(-/-) knockout (KO) mice through homologous recombination in mouse embryonic stem cells. Tk KO mice have shortened life spans compared with their wild-type or Tk heterozygous (HET) siblings. All Tk KO mice develop sclerosis of kidney glomeruli and die before one year of age of kidney failure. Among other changes in KO animals, the most consistent is a switch from exclusively mucous secretion to predominantly serous secretion in the sublingual salivary gland. HET parents can produce KO mice at a frequency approaching Mendelian inheritance. Other observations in KO animals include an elevated level of serum thymidine, a significant decrease in the cloning efficiency of splenic lymphocytes, an increase in the frequency of hypoxanthine guanine phosphoribosyl transferase gene mutant lymphocytes, and histological alteration in the lymphoid structure of the spleen. In addition, KO animals sporadically exhibit inflammation of the arteries, which taken together with the lymphocyte and spleen abnormalities, suggest an abnormal immune system. Alterations in Tk KO mice indicate that the pyrimidine nucleotide salvage pathway is indispensable in vivo. (C) 2002 Elsevier Science (USA). All rights reserved.