Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35)
Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35)
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DOI：
10.1007/s00439-009-0736-4
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发表时间：
2010-01-01
期刊：
影响因子：
5.3
通讯作者：
Morton, Cynthia C.
中科院分区：
文献类型：
--
作者：
Brown, Kerry K.;Reiss, Jacob A.;Morton, Cynthia C.
精确调节基因表达的时间和空间模式对人类的正常发育至关重要。顺式调控元件，其中一些位于离相应基因很远的地方，在关键发育基因的转录控制中起关键作用，这些调控元件的破坏可导致疾病。我们报告了一个三代家族，有五名患病成员，他们都有听力损失，颅面缺陷和7号染色体长臂的顺中心倒置，inv(7)（q21.3q35）。高分辨率反演图显示，7q21.3断点分别位于DLX6和DLX5的65和80 kb中心点处。进一步分析显示，在7q21.3断点处有5115 bp的缺失。虽然断点不会破坏DLX5或DLX6，但该家族中存在的综合征与在DLX5敲除小鼠中观察到的综合征相似，并且包括在DLX5和DLX6缺失个体中观察到的特征子集，这暗示了该家族表型中DLX5和DLX6的失调。生物信息学分析表明，7q21.3断点处5115 bp的缺失可能包含DLX5和DLX6表达所需的调控元件。通过转基因小鼠报告基因实验，我们发现缺失的序列可以在E12.5胚胎的内耳和发育中的骨骼中驱动表达。因此，观察到的家族性综合征可能是由特定组织中DLX5和/或DLX6的失调引起的，这是由于一个增强子的缺失，以及可能通过染色体反转与其他调节元件分离。
Precisely regulated temporal and spatial patterns of gene expression are essential for proper human development. Cis-acting regulatory elements, some located at large distances from their corresponding genes, play a critical role in transcriptional control of key developmental genes and disruption of these regulatory elements can lead to disease. We report a three generation family with five affected members, all of whom have hearing loss, craniofacial defects, and a paracentric inversion of the long arm of chromosome 7, inv(7)(q21.3q35). High resolution mapping of the inversion showed that the 7q21.3 breakpoint is located 65 and 80 kb centromeric of DLX6 and DLX5, respectively. Further analysis revealed a 5,115 bp deletion at the 7q21.3 breakpoint. While the breakpoint does not disrupt either DLX5 or DLX6, the syndrome present in the family is similar to that observed in Dlx5 knockout mice and includes a subset of the features observed in individuals with DLX5 and DLX6 deletions, implicating dysregulation of DLX5 and DLX6 in the family's phenotype. Bioinformatic analysis indicates that the 5,115 bp deletion at the 7q21.3 breakpoint could contain regulatory elements necessary for DLX5 and DLX6 expression. Using a transgenic mouse reporter assay, we show that the deleted sequence can drive expression in the inner ear and developing bones of E12.5 embryos. Consequently, the observed familial syndrome is likely caused by dysregulation of DLX5 and/or DLX6 in specific tissues due to deletion of an enhancer and possibly separation from other regulatory elements by the chromosomal inversion.