Mouse models of human phenylketonuria.
Mouse models of human phenylketonuria.
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发表时间：
1993-08
期刊：
影响因子：
3.3
通讯作者：
A. Shedlovsky;J. McDonald;D. Symula;W. Dove
中科院分区：
文献类型：
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作者：
A. Shedlovsky;J. McDonald;D. Symula;W. Dove
苯丙酮尿症（PKU）是由苯丙氨酸羟化酶（催化苯丙氨酸（PHE）转化为酪氨酸的酶）缺乏引起的。虽然这种先天性代谢缺陷是人类首先被生化和遗传学理解的，但对PKU病理学中涉及的机制知之甚少。我们结合小鼠种系诱变筛选高苯丙氨酸血症，分离三个突变体缺乏苯丙氨酸羟化酶（PAH）的活性和交叉反应蛋白。其中两种具有减少的PAH mRNA和未治疗的人PKU患者的显示特征。低PHE饮食部分逆转这些异常。我们在使用高频率随机生殖系点突变获得适当的疾病模型中的成功说明了这种突变如何能够补充小鼠中靶向突变的应急能力。突变体可作为研究母体PKU和体细胞基因治疗的模型。
Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy.