Comparative genetics of Lesch-Nyhan disease

描述(由申请人提供)：确定疾病易感性的基因对人类健康至关重要。同样重要的是识别赋予疾病抵抗力的基因。这项R21提案的目标是在小鼠身上从遗传学和分子水平上评估对一种名为Lesch-Nyhan病的人类遗传病的抗性候选基因。Lesch-Nyhan病是一种由嘌呤抢救酶次黄嘌呤磷酸核糖基转移酶(HPRT1)缺乏引起的先天性代谢错误，可导致严重的发育、神经和行为障碍，目前尚无治愈方法。与HPRT1缺乏症对人类的深远影响不同，小鼠HPRT1活性的丧失不会导致HPRT1缺乏症患者出现严重的临床表型。因此，由于小鼠对莱施-尼汉病的抗性，它们提供了一个识别基因(S)的模型系统，该基因可以抑制这种人类遗传疾病的严重临床症状。我们最近发现了一个新的候选基因，它可能导致抑制小鼠的Lesch-Nyhan病的表型。具体地说，在HPRT1基因家族中的一个未知成员PRTFDC1中，只在小鼠中发现了基因失活事件。因此，鉴于HPRT1和PRTFDC1的相似性，我们假设人类和小鼠之间的这种基因含量的差异有助于这些物种对Lesch-Nyhan病相关的严重临床表型的不同易感性。为了验证这一假设，表达PRTFDC1的人源化转基因小鼠将被用来评估HPRT1缺陷小鼠中该基因的表达是否会导致与Lesch-Nyhan病相关的严重临床表型的表现。此外，PRTFDC1和HPRT1之间的调控相互作用将通过基因表达和蛋白质分析来表征。总而言之，目前还没有合适的Lesch-Nyhan病动物模型。本文提出的实验将从遗传学和分子水平评估调节HPRT1缺乏症的物种间易感性的候选基因，以此作为建立新的Lesch-Nyhan病动物模型的手段，并剖析这种先天性代谢错误的基本病因学。

DESCRIPTION (provided by applicant): The identification of genes underlying disease susceptibility is of critical importance to human health. Equally important is the identification of genes that confer resistance to disease. The goal of this R21 proposal is to genetically and molecularly evaluate a candidate gene for the resistance to a human genetic disease, called Lesch-Nyhan disease, in mice. Lesch-Nyhan disease is an inborn error in metabolism caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT1), and leads to severe developmental, neurological, and behavioral disorders for which there is no cure. In contrast to the profound effect HPRT1-deficiency has in humans, loss of HPRT1 activity in mice does not result in the severe clinical phenotypes seen in HPRT1-deficient patients. Thus, because of their resistance to Lesch-Nyhan disease, mice provide a model system for identifying the gene(s) that can suppress the severe clinical symptoms of this human genetic disorder. We recently identified a novel candidate gene which could lead to the suppression of the Lesch-Nyhan disease phenotypes in mice. Specifically, a gene inactivation event in an uncharacterized member of the HPRT1-gene family, PRTFDC1, was found only in mice. Therefore, given the similarity of HPRT1 and PRTFDC1, we hypothesize that this difference in gene content between humans and mice contributes to the differential susceptibility these species have to the severe clinical phenotypes associated with Lesch-Nyhan disease. In order to test this hypothesis, 'humanized' transgenic mice expressing PRTFDC1 will be used to evaluate if expression of this gene in HPRT1-deficient mice leads to the manifestation of the severe clinical phenotypes associated with Lesch-Nyhan disease. In addition, the regulatory interactions between PRTFDC1 and HPRT1 will be characterized by gene expression and protein assays. In summary, there is no adequate animal model of Lesch-Nyhan disease. The experiments proposed here will genetically and molecularly evaluate a candidate gene for modulating the interspecies susceptibility to HPRT1-deficiency as a means to develop a novel animal model of Lesch-Nyhan disease, and dissect the basic etiology of this inborn error in metabolism.