Comparative genetics of Lesch-Nyhan disease

描述（由申请人提供）：鉴定疾病易感性相关基因对人类健康至关重要。同样重要的是鉴定赋予抗病性的基因。这项R21提案的目标是从遗传学和分子学上评估一种候选基因，用于抵抗小鼠中的人类遗传疾病，称为Lesch-Nyhan病。莱-尼二氏病是一种先天性代谢缺陷，由嘌呤补救酶次黄嘌呤磷酸核糖转移酶（HPRT 1）缺乏引起，并导致严重的发育、神经和行为障碍，目前尚无治愈方法。与HPRT 1缺陷在人类中的深远影响相反，小鼠中HPRT 1活性的丧失不会导致HPRT 1缺陷患者中观察到的严重临床表型。因此，由于它们对莱施-尼汉病的抗性，小鼠提供了用于鉴定可以抑制这种人类遗传性疾病的严重临床症状的基因的模型系统。我们最近发现了一种新的候选基因，它可能导致小鼠莱施-尼汉病表型的抑制。具体而言，一个基因失活事件中的一个未知成员的HPRT 1基因家族，PRTFDC 1，只在小鼠中发现。因此，考虑到HPRT 1和PRTFDC 1的相似性，我们假设人类和小鼠之间基因含量的差异导致了这些物种对与Lesch-Nyhan病相关的严重临床表型的不同易感性。为了检验这一假设，将使用表达PRTFDC 1的“人源化”转基因小鼠来评价该基因在HPRT 1缺陷型小鼠中的表达是否导致与Lesch-Nyhan病相关的严重临床表型的表现。此外，PRTFDC 1和HPRT 1之间的调节相互作用将通过基因表达和蛋白质测定来表征。总之，目前还没有足够的Lesch-Nyhan病动物模型。这里提出的实验将从遗传学和分子学上评估一个候选基因，用于调节HPRT 1缺陷的种间易感性，以开发一种新的Lesch-Nyhan病动物模型，并剖析这种先天性代谢缺陷的基本病因。

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.