Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.
Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.
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DOI：
10.1093/hmg/dds241
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发表时间：
2012-09
影响因子：
3.5
通讯作者：
M. Wat;Tyler Beck;A. Hernandez-Garcia;Zhiyin Yu;D. Veenma;Monica D. Garcia;A. Holder;J. Wat;Yuqing Chen;C. Mohila;K. Lally;M. Dickinson;D. Tibboel;A. de Klein;Brendan H. Lee;D. Scott
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文献类型：
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作者：
M. Wat;Tyler Beck;A. Hernandez-Garcia;Zhiyin Yu;D. Veenma;Monica D. Garcia;A. Holder;J. Wat;Yuqing Chen;C. Mohila;K. Lally;M. Dickinson;D. Tibboel;A. de Klein;Brendan H. Lee;D. Scott
包括GATA 4和SOX 7的8p23.1的复发性微缺失赋予先天性膈疝（CDH）和心脏缺陷的高风险。虽然GATA 4缺陷小鼠同时具有CDH和心脏缺陷，但没有人报告患有归因于GATA 4突变的心脏缺陷。我们也不能确定CDH队列中有害的GATA 4序列变化。这表明另一个8p23.1基因的单倍不足可能与GATA 4沿着促进CDH的发展。为了确定另一种转录因子编码基因SOX 7的单倍不足是否有助于CDH的发展，我们产生了Sox 7第二外显子缺失的小鼠。这些Sox 7（Δ ex 2/+）小鼠中的一部分发生了位于膈肌前肌部分的胸骨后疝。前部CDH也见于Gata 4（+/-）小鼠中，并且已被描述为与人类中的8p23.1缺失相关。免疫组化结果显示，SOX 7在发育中的膈肌血管内皮细胞中表达，在某些膈肌细胞中可能有弱表达。Sox 7（Δ ex 2/Δ ex 2）胚胎在隔膜发育前死亡，心包囊扩张，卵黄囊重塑失败，提示心血管衰竭。与我们筛选GATA 4的经验相似，在我们的CDH队列中未发现明显有害的SOX 7序列变化。我们的结论是，单倍不足的Sox 7或GATA 4是足以产生前CDH小鼠和SOX 7和GATA 4的单倍不足可能各自有助于CDH的发展与8p23.1缺失的个人。
Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4-deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4, to the development of CDH. To determine if haploinsufficiency of SOX7-another transcription factor encoding gene-contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7. A portion of these Sox7(Δex2/+) mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4(+/-) mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7(Δex2/Δex2) embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4, no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions.