14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements
14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements
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DOI：
10.1038/ejhg.2012.127
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发表时间：
2012-12-01
影响因子：
5.2
通讯作者：
Philippe, Christophe
中科院分区：
文献类型：
--
作者：
Allou, Lila;Lambert, Laetitia;Philippe, Christophe
Forkhead box G1（FOXG 1）基因与严重的Rett样表型有关。它编码叉头盒蛋白G1，一种对前脑发育至关重要的翼螺旋转录抑制因子。最近，核心FOXG 1综合征被定义为出生后小头畸形，严重的精神发育迟滞，语言缺失，运动障碍和胼胝体发育不全。我们提出了另外7例与从头FOXG 1点突变（2例）或14 q12缺失（5例）相关的严重Rett样神经发育障碍患者。我们扩大了FOXG 1相关脑病患者的突变谱，并精确了核心FOXG 1综合征表型。胼胝体发育不良和运动障碍并不总是存在于FOXG 1突变的患者。我们认为，FOXG 1基因应考虑在严重的智障患者（无语言），严重获得性小头畸形（-4至-6 SD）和少数临床特征提示Rett综合征。有趣的是，三个不包括FOXG 1基因的14 q12缺失与FOXG 1突变阳性患者的表型非常相似。我们物理映射一个假定的长距离FOXG 1调控元件在一个0.43 Mb的DNA片段，包括PRKD 1基因座。在成纤维细胞中，一个顺式作用的调控序列位于超过0.6 Mb远离FOXG 1作为一个沉默子在转录水平。这些数据对于临床医生和参与管理与FOXG 1相关表型相容的严重脑病患者的分子生物学家非常重要。European Journal of Human Genetics（2012）20，1216-1223; doi：10.1038/ejhg.2012.127; 2012年6月27日在线发表
The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to -6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype. European Journal of Human Genetics (2012) 20, 1216-1223; doi:10.1038/ejhg.2012.127; published online 27 June 2012