Gross deletions involving IGHM, BTK, or Artemis:: A model for genomic lesions mediated by transposable elements
Gross deletions involving IGHM, BTK, or Artemis:: A model for genomic lesions mediated by transposable elements
复制标题
DOI：
10.1016/j.ajhg.2007.10.011
复制
发表时间：
2008-02-01
影响因子：
9.8
通讯作者：
van der Burg, Mirjarn
中科院分区：
文献类型：
--
作者：
van Zelm, Menno C.;Geertsema, Corinne;van der Burg, Mirjarn
大多数人类疾病的遗传破坏是微小病变，而肉眼病变是罕见的，肉眼缺失是最常见的（6%）。在原发性免疫缺陷基因（如BTK）中也观察到了类似的结果，但由于未知原因，IGHM和DCLRE 1C（Artemis）基因缺陷经常表现为严重缺失（类似于60%）。我们在IGHM、BTK和Artemis缺陷患者中描述了粗缺失断点。IGHM缺失断点未显示重组信号序列或免疫球蛋白开关区的参与。相反，5 IGHM，8 BTK，和5个独特的Artemis断点位于或附近的序列来自转座因子（TE）。5个Artemis等位基因中有4个的断裂点位于高度同源区域，与IG亚类缺陷和V-H缺失多态性相似。然而，这些观察结果表明TE在介导总缺失中的作用。所鉴定的总缺失断点大多位于TE亚类中，与人类基因组中的平均值相比，所述TE亚类在所涉及的基因中特异性过度表达。这涉及长（LINE 1）和短（Alu，MIR）散布元件，以及LTR反转录转座子（ERV）。此外，高的总TE含量（>40%）与总缺失频率的增加相关。这两项发现在人类疾病中被破坏的总共20个基因中得到了进一步的研究和证实。因此，据我们所知，我们第一次提供的证据表明，高TE含量，无论类型的元素，结果在总缺失的发病率增加作为基因破坏人类疾病的基础。
Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions (similar to 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and V-H deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease.