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Nature Genetics：研究发现引发红斑狼疮的基因突

2015-04-25 01:10 毕业

    生物谷报道：最近，美国威克森林大学医学院的科学家们发现了与系统性红斑狼疮及其相关自身免疫性疾病有关的基因TREX1。这项发表在《自然遗传学》上的报告，是1系列有关揭示此类疾病的细胞异常的最新发现。研究者们希望通过对该基因突变和相关蛋白结构的深入了解可以开发出有效的药物治疗来抑制突变基因的激活。
    该文的第1作者、来自德国Technische Universität Dresden的Min Ae Lee-Kirsch, M.D.和他的同事们报道，从系统性红斑狼疮患者体内发现的TREX1基因上，他们发现了相关的变异。研究包括了来自英国和德国的417名狼疮患者，发现其中有9名患者带有这种基因突变，而1712名非狼疮患者则1个都没有发现。这个基因能够产生TREX1蛋白，后者的功能就是分解或解开控制细胞内各种过程的遗传物质DNA。分解过程发生在细胞死亡和更新的自然程序中，如果DNA 在细胞死亡的过程中不能更新或是解链，体内就会产生相应的抗体。如果TREX1蛋白不能将DNA解链，那您的身体就会产生针对你体内DNA 的抗体，结果就是发生狼疮等疾病。
    威克森林大学生物化学教授同时也是这篇文章的合作者Fred Perrino, Ph.D说：“这项研究对于明确狼疮及其相关的自身免疫性疾病是1个很大的飞跃，在此之前，相关的线索很少。我们都知道狼疮是1个复杂的疾病，但是现在我们发现了1个特殊的蛋白和1个特定的细胞过程（process），它们很可能是疾病的发病原因，我们正在试图将所有的线索联系起来去发现疾病的生物学基础。” 发表在4月份《生物化学杂志》上的1个报道显示，有研究者发现该基因的3个变异使TREX1蛋白的活力减少到40，000至35，000分之1。 （科教作文网http://zw.nseAc.com）
    在近几年，还发现这个基因与1种在婴儿期就致死的罕见的神经疾病Aicardi-Goutieres综合征有关；也与冻疮样狼疮有关，该病是1种遗传性疾病，表现为在寒冷天气发生的痛性皮肤蓝红斑，通常在夏天会缓解；研究显示该基因也与干燥综合征有关，它是狼疮的分型之1（a form of lupus）。

 

原文出处:

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus

Min Ae Lee-Kirsch, Maolian Gong, Dipanjan Chowdhury, Lydia Senenko, Kerstin Engel, Young-Ae Lee, Udesh de Silva, Suzanna L Bailey, Torsten Witte, Timothy J Vyse, Juha Kere, Christiane Pfeiffer, Scott Harvey, Andrew Wong, Sari Koskenmies, Oliver Hummel, Klaus Rohde, Reinhold E Schmidt, Anna F Dominiczak, Manfred Gahr, Thomas Hollis, Fred W Perrino, Judy Lieberman & Norbert Hübner

Published online: 29 July 2007; | doi:10.1038/ng2091

Abstract  | Full Text  | PDF (260 KB)  | Supplementary information

 

 

作者简介：

Experimential Genetics of Cardiovascular Diseases, Prof. Dr. Norbert Hübner

Analysis of complex cardiovascular diseases in the rat

（转载自中国科教评价网www.nseac.com ）

The rat is one of the most important model systems for complex, polygenic diseases. Since all epidemiologically important human diseases belong to this category, the potential for major advances through genetic investigation is substantial.

We have demonstrated that multiple chromosomal loci in rat models contribute to blood pressure regulation and hypertension. Independent from elevated blood pressure, additional genetic factors contribute to end-organ damage and stroke in these animals. Ongoing research in our laboratory is directed towards the identification of the underlying predisposing genes and the subsequent identification of their molecular variants, which cause cardiovascular disorders.

To localize disease genes within chromosomal regions linked to quantitative traits (e.g. blood pressure), we are establishing multiple congenic rat strains by introgressing disease alleles encompassing the quantitative trait locus (QTL) into a nonaffected reference strain by successive backcrossing and molecular analysis. This strategy allows the observation of the effect and the genetic analysis of a single QTL. We are currently applying this strategy to a number of QTLs for blood pressure regulation, stroke, and kidney disease in the stroke-prone spontaneously hypertensive rat.

The combination of congenic experimentation with the development of subcongenic animals, with only a fraction of the initial congenic segment will enable successive fine mapping within a QTL. The mapping efforts of complex cardiovascular traits by congenic experimentation and positional cloning will be used in ongoing projects jointly with the establishment of gene expression signatures in target organs of congenic animals and their parental progenitors. High density microarrays are used for this approach. A combinatorial approach of positional cloning and expression profiling will provide a powerful tool to identify positional candidate genes within chromosomal regions for genetically determined cardiovascular diseases.

These data are being used to identify clusters of genes that cosegregate with well-documented cardiovascular and metabolic phenotypes within spontaneously hypertensive rats and to identify the underlying allelic variants. By determining the genetic networks and regulatory mechanisms underlying the observed patterns of gene expression, these data will provide new insights into the control mechanisms for hypertension, insulin resistance, and associated metabolic phenotypes that may be shared in common with similar disorders in humans.

The identification of disease-relevant genes within QTLs by positional cloning will be greatly facilitated once the sequence of the entire rat genome is known. Moreover, functional studies often require access to clones in specific regions of interest. We have thus participated in the Rat Genome Sequencing Project Consortium, which resulted in the identification and annotation of the entire rat genome sequence. Additionally, we have built a physical map based on Yeast Artifical Chromosomes (YAC) and Bacterial Artifical Chromosomes (BAC). Combined this map comprises more then 200,000 BAC and YAC clones which are all anchored to the genomic sequence. These clones provide ready access to any genomic region for functional studies.

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