Tissue-specific aberrations of gene expression in HPRT-deficient mice: functional complexity in a monogenic disease?
Tissue-specific aberrations of gene expression in HPRT-deficient mice: functional complexity in a monogenic disease?
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HPRT缺陷小鼠中基因表达的组织特异性畸变：单基因疾病的功能复杂性？
DOI：
10.1038/sj.mt.6300199
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Friedmann,Theodore
中科院分区：
文献类型：
--
作者：
Song,Shaochun;Friedmann,Theodore
我们使用次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HPRT）酶缺陷小鼠模型的人莱施-尼汉病（LND），以检查改变的全球基因表达的组织特异性在遗传上的“简单”的单基因人类疾病。我们已经鉴定了在LND的小鼠敲除模型中表达异常的许多基因和基因家族，并且我们已经鉴定了与疾病表型相关的两种主要靶组织中异常基因表达的不同模式，即，中枢神经系统和肝脏。主要的神经系统表型反映了基底神经节多巴胺神经递质系统的功能障碍，我们现在已经确定了HPRT缺陷纹状体中少数基因的异常表达。HPRT缺陷小鼠中高尿酸血症的异常代谢表型也反映在肝脏中的异常基因表达中。我们解释这些发现表明，在小鼠中的主要HPRT基因敲除的遗传后果产生转录畸变的一些其他基因，可能在疾病表型中发挥作用。了解这些继发性遗传缺陷可能有助于确定药物和基因治疗的靶点。
We have used the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme-deficient mouse model of human Lesch-Nyhan disease (LND) to examine the tissue-specificity of altered global gene expression in a genetically "simple" monogenic human disease. We have identified a number of genes and gene families whose expression is aberrant in the mouse knockout model of the LND, and we have identified different patterns of aberrant gene expression in two principal target tissues associated with the disease phenotype,i.e.,the central nervous system and the liver. The major neurological phenotype reflects dysfunction of the dopamine neurotransmitter system in the basal ganglia, and we have now identified aberrant expression of a small number of genes in HPRT-deficient striata. The abnormal metabolic phenotype of hyperuricemia in HPRT-deficient mice is also reflected in an aberrant gene expression in the liver. We interpret these findings to suggest that the genetic consequences of a primary HPRT knockout in the mouse produces transcriptional aberrations in a number of other genes that may play a role in the disease phenotype. Knowledge of these secondary genetic defects may help in the identification of targets for drug- and gene-based therapy.