Nature Genetics：研究发现引发红斑狼疮的基因突变

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
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.

Anchoring of fingerprint and YAC map regions to sequence assembly. YAC contigs are anchored to the assembly by way of hybridizations to BACs with sequence coordinates. The sequence coverage of anchoring BACs is typically less than the estimated size of the YAC contigs and therefore the contigs as drawn do not reflect actual size. Light grey lines link regions that are (a) are anchored by hybridization to a single BAC that is associated with < 80% of the contig YACs or (b) are anchored by <20% of the contig BACs, leading to spurios contig segmentation on the assembly not likely to be dueto actual inconsistencies between the YAC map and the sequence assemly. Red lines link the remaining region pairs, for which segmentation evidence is robust.

See also our homepage:
http://www.mdc-berlin.de/ratgenom/

相关基因：

TREX1

Official Symbol TREX1 and Name: three prime repair exonuclease 1 [Homo sapiens]
Other Aliases: AGS1, AGS5, CREN, DKFZp434J0310, DRN3
Other Designations: 3' repair exonuclease 1; Aicardi-Goutieres syndrome 1; Cree encephalitis; deoxyribonuclease III, dnaQ/mutD (E. coli)-like
Chromosome: 3; Location: 3p21.3-p21.2
MIM: 606609
GeneID: 11277

相关报道：

系统性红斑狼疮(systemic lupus erythematosus)(SLE)12 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)11

系统性红斑狼疮(systemic lupus erythematosus)(SLE)10

系统性红斑狼疮(systemic lupus erythematosus)(SLE)09 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)08 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)07 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)06

系统性红斑狼疮(systemic lupus erythematosus)(SLE)05 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)04 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)03 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)02 

系统性红斑狼疮(systemic lupus erythematosus)(SLE)01