Evidence against the current hypothesis of "gene dosage effects" of trisomy 21: ets-2, encoded on chromosome 21" is not overexpressed in hearts of patients with Down Syndrome
Evidence against the current hypothesis of "gene dosage effects" of trisomy 21: ets-2, encoded on chromosome 21" is not overexpressed in hearts of patients with Down Syndrome
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DOI：
10.1006/bbrc.1998.9743
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发表时间：
1999-01-19
影响因子：
3.1
通讯作者：
Lubec, G
中科院分区：
文献类型：
--
作者：
Greber-Platzer, S;Schatzmann-Turhani, D;Lubec, G
背景：包括先天性心脏病(CHD)在内的唐氏综合征(DS)表型的发病机制目前的主要概念是所谓的“基因剂量效应”。根据这一假说，21号染色体“临界区”(被认为对DS表型的发展至关重要)编码的基因在三体状态下过度表达，从而导致原癌基因Ets-2、超氧化物歧化酶等基因的失衡。方法：我们研究了6例DS和7例先天性心脏病患者的手术心脏活检组织。通过竞争性逆转录聚合酶链式反应(RT-PCR)技术检测Ets-2-mRNA的稳态水平，该技术允许在attomol水平上检测该基因。结果：DS患者总心室组织中ETS-2mRNA的浓度为0.60+/-0.42fg/10 ng总RNA(平均值，+/-SD)。当与看家基因Betaactin对照以排除该疾病的一般转录变化时，计算比值0.56+/-0.28(平均值，+/-SD)，非DS CHD患者总心室组织中Ets-2mRNA的浓度为0.45+/-0.22 fg/10 ng总RNA(平均值，+/-SD)，比值为0.48+/-0.35(平均值，+/-SD)。在P<；0.05水平上没有发现差异。结论：到目前为止，还没有对“基因剂量效应假说”中涉及的基因进行绝对定量，而且唯一一种利用Northern印迹法(Northern Blotting)对ETS-e基因进行(半)定量测定的方法只发表在一个单独的DS样本上。这是第一个清楚地表明在DS患者的心脏中没有发现Ets-2过度表达的报告，从而为反对当前的基因剂量效应假说提供了证据。(C)1999年学术出版社。
Background: The major current concept for the pathogenesis of the Down Syndrome (DS) phenotype including congenital heart disease (CHD) is the so-called "gene dosage effect." According to this hypothesis, genes encoded by chromosome 21 at the "critical region" (which is thought to be crucial for the development of the DS phenotype) are overexpressed in the trisomic state, thus leading to an imbalance of genes as, e.g., the protooncogene ets-2, superoxide dismutase, etc. Methods: We studied heart biopsies obtained at surgery from 6 patients with DS and 7 patients with congenital heart disease. ets-2-mRNA steady state levels were determined by a competitive reverse transcription-polymerase chain reaction (RT-PCR) technique which allowed the determination of this gene at the attomol level. Results: ets-2 mRNA in total ventricular tissue of DS patients showed concentrations of 0.60 +/- 0.42 fg/10 ng total RNA (mean, +/- SD). When normalized versus the housekeeping gene betaactin to rule out general transcriptional changes in that disorder, the ratio of 0.56 +/- 0.28 (mean, +/- SD) was calculated, ets-2 mRNA in total ventricular tissue of patients with non-DS CHD showed concentrations of 0.45 +/- 0.22 fg/10 ng total RNA (mean, +/- SD) and ratios of 0.48 +/- 0.35 (mean, +/- SD). No differences could be found at the p < 0.05 level. Conclusion: No absolute quantification of a gene incriminated in the "gene dosage effect-hypothesis" was performed so far and the only approach to (semi-) quantitative determination of the ets-e gene using northern blotting was published on one individual DS sample only. This is the first report to clearly show that no overexpression of ets-2 can be found in heart of patients with DS, thus providing evidence against the current gene dosage effect-hypothesis. (C) 1999 Academic Press.