Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS19
Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS19
复制标题
DOI：
10.1371/journal.pone.0006172
复制
发表时间：
2009-07-09
期刊：
影响因子：
3.7
通讯作者：
Schuster, Jens
中科院分区：
文献类型：
--
作者：
Barrio, Alvaro Martinez;Eriksson, Oskar;Schuster, Jens
背景资料：核糖体蛋白S19基因座（RPS 19）与两种红细胞再生障碍性贫血（DBA）和儿童期短暂性成红细胞减少症（TEC）有关。在25%的DBA患者中发现了RPS 19编码序列的突变，但在TEC患者中没有发现。有人认为，非编码RPS 19序列变体导致红细胞再生障碍性贫血的相当大的临床变异性。因此，我们的目的是在确定非编码变异与DBA或TEC phenotypes.Methodology/主要发现：我们有针对性的区域19'980 bp的RPS 19基因在一个队列中的89 DBA和TEC患者进行重测序。我们在这里提供了一个目录的相当大的，以前没有认识到的程度的变化，在这个地区。我们鉴定了73个变异（65个SNP，8个插入缺失），它们都位于RPS 19开放阅读框架之外，其中67.1%被归类为新的。我们推测RPS 19非编码区的特定等位基因可以改变调节蛋白或转录因子的结合。因此，我们进行了广泛的分析，以确定转录因子结合位点（TFBS）。一系列假定的相互作用位点与检测到的变体一致。16个相应的转录因子是特别感兴趣的，因为它们是管家基因或显示出与造血、肿瘤发生或白血病的直接联系（例如，G.加塔-1/2，PU. 1，MZF-1）。结论：预测TFBS的特异性等位基因可能改变RPS 19的表达，修饰具有重叠TFBS的转录因子之间的重要相互作用或去除造血的重要刺激。我们认为，检测到的相互作用是造血的重要性，并可以提供新的见解个人对治疗的反应。
Background: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes.Methodology/Principal Findings: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e. g. GATA-1/2, PU.1, MZF-1).Conclusions: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.