Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
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DOI：
10.1093/hmg/ddn097
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Ishii, Isao
中科院分区：
文献类型：
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作者：
Akahoshi, Noriyuki;Kobayashi, Chiho;Ishii, Isao
胱硫醚β-合酶缺陷小鼠（Cbs（-/-））表现出与高同型半胱氨酸血症患者相似的几种病理生理学特征，包括内皮功能障碍和肝脂肪变性。C57 BL/6 J背景下的杂合突变体（Cb（+/-））在世界各地的实验室中进行了广泛分析;然而，Cb（-/-）的详细分析受到阻碍，因为它们很少存活超过断奶年龄，这可能是由于严重的肝功能障碍。将突变体与4个近交系（C57 BL/6 J（Jcl）、BALB/cA、C3 H/HeJ和DBA/2 J）回交7代，比较不同遗传背景下的Cbs（-/-）表型。尽管所有背景的Cbs（-/-）在2周龄时都是高同型半胱氨酸血症/高甲硫氨酸血症并患有脂肪变性/肝脂肪变性，但> 30%的C3 H/HeJ-Cbs（-/-）存活超过8周，而DBA/2 J-Cbs（-/-）没有存活超过5周。在2周时，血清总同型半胱氨酸和甘油三酯水平在C3 H/HeJ-Cbs（-/-）中最低。成年C3 H/HeJ-Cb（-/-）存活者表现为高同型半胱氨酸血症，但未发生高甲硫氨酸血症、肝硬化和肝脂肪变性。它们在一般行为测试中表现正常，但在被动回避避暗测试中表现出小脑畸形和学习能力受损，并且需要足够的饮食补充半胱氨酸才能生存，这证明了胱硫醚β-合酶在中枢神经系统功能和半胱氨酸生物合成中的重要作用。我们的C3 H/HeJ-Cbs（-/-）小鼠可能是有用的工具，用于研究临床症状，如精神发育迟滞和血栓栓塞，发现在同型半胱氨酸患者。
Cystathionine beta-synthase-deficient mice (Cbs(-/-)) exhibit several pathophysiological features similar to hyperhomocysteinemic patients, including endothelial dysfunction and hepatic steatosis. Heterozygous mutants (Cbs(+/-)) on the C57BL/6J background are extensively analyzed in laboratories worldwide; however, detailed analyses of Cbs(-/-) have been hampered by the fact that they rarely survive past the weaning age probably due to severe hepatic dysfunction. We backcrossed the mutants with four inbred strains (C57BL/6J(Jcl), BALB/cA, C3H/HeJ and DBA/2J) for seven generations, and compared Cbs(-/-) phenotypes among the different genetic backgrounds. Although Cbs(-/-) on all backgrounds were hyperhomocysteinemic/hypermethioninemic and suffered from lipidosis/hepatic steatosis at 2 weeks of age, > 30% of C3H/HeJ-Cbs(-/-) survived over 8 weeks whereas none of DBA/2J-Cbs(-/-) survived beyond 5 weeks. At 2 weeks, serum levels of total homocysteine and triglyceride were lowest in C3H/HeJ-Cbs(-/-). Adult C3H/HeJ-Cbs(-/-) survivors showed hyperhomocysteinemia but escaped hypermethioninemia, lipidosis and hepatic steatosis. They appeared normal in general behavioral tests but showed cerebellar malformation and impaired learning ability in the passive avoidance step-through test, and required sufficient dietary supplementation of cyst(e)ine for survival, demonstrating the essential roles of cystathionine beta-synthase in the central nervous system function and cysteine biosynthesis. Our C3H/HeJ-Cbs(-/-) mice could be useful tools for investigating clinical symptoms such as mental retardation and thromboembolism that are found in homocysteinemic patients.