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首页> 外文期刊>American journal of medical genetics, Part A >Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins
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Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins

机译：致命性肺泡毛细血管发育不良伴肺静脉错位的情况下FOXF1的倒位

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Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a congenital malformation that leads to severe pulmonary hypertension and respiratory failure. It has been associated with deletion of, or mutation in, FOXF1 on 16q24.1, a gene encoding a forkhead transcription factor expressed in the mesenchyme of the developing lung. Here we report on the identification of a pericentric inversion on chromosome 16 (p11.2q24.1) in a case of lethal ACDMPV with atrioventricular septal defect and duodenal atresia. Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134±10kb upstream (5′; centromeric) of FOXF1. This is suggestive of cis-regulatory elements located more than 130kb 5′ of FOXF1, and analysis of genome-wide data sets of chromatin modifications in two different cell types suggested that the FOXF1 regulatory domain covers more than 300kb, and perhaps up to 433kb, upstream of the gene, but only 3kb downstream. The 588kb gene-free region between FOXF1 and the next gene in the centromeric direction, IRF8, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of FOXF1. Our results further strengthen the association between FOXF1 and a spectrum of malformations that include ACDMPV, atrioventricular septal defects, and gastrointestinal atresia. Furthermore, the presented analysis aids in defining the critical genomic region for this syndrome.
机译：肺静脉未对准的肺泡毛细血管发育不良（ACDMPV）是一种先天性畸形，可导致严重的肺动脉高压和呼吸衰竭。它与16q24.1上的FOXF1缺失或突变有关，该基因编码在发育中的肺的间充质中表达的叉头转录因子。在这里，我们报告了在致命性ACDMPV并伴有房室间隔缺损和十二指肠闭锁的情况下，在16号染色体（p11.2q24.1）上发生了周围性反转的鉴定。 Array-CGH表明反转是平衡的，FISH表明q臂断点出现在FOXF1上游134±10kb（5';着丝粒）。这表明FOXF1的130'5'端有顺式调控元件，对两种不同细胞类型的染色质修饰的全基因组数据集的分析表明，FOXF1调控域覆盖了300kb以上，也许高达433kb，基因上游，但仅下游3kb。 FOXF1和着丝粒方向下一个基因IRF8之间的588kb无基因区域在物种之间高度保守，并通过绝缘子元件分为两个不同的调控域。另一个假定的绝缘子出现在FOXF1的下游。我们的结果进一步加强了FOXF1与包括ACDMPV，房室间隔缺损和胃肠道闭锁在内的一系列畸形之间的关联。此外，提出的分析有助于确定该综合征的关键基因组区域。

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