Cavallin Mara, Maillard Camille, Hully Marie, Philbert Marion, Boddaert Nathalie, Reilly Madeline Louise, Nitschké Patrick, Bery Amandine, Bahi-Buisson Nadia
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology APHP- Necker Enfants Malades University Hospital, Paris, France.
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology APHP- Necker Enfants Malades University Hospital, Paris, France.
Eur J Med Genet. 2018 Dec;61(12):729-732. doi: 10.1016/j.ejmg.2018.05.002. Epub 2018 May 25.
Postnatal microcephaly comprises a heterogeneous group of neurodevelopmental disorders of varying severity, characterized by normal head size at birth, followed by a postnatal deceleration in head circumference of greater than 3 standard deviations (SD) below the mean. Many postnatal microcephaly syndromes are caused by mutations in genes known to be important for the regulation of gene expression in the developing forebrain. We studied a consanguineous Pakistani family with postnatal microcephaly, orofacial dyskinesia, spastic quadriplegia and, on MRI, cortical atrophy with myelination delay, suggestive of a FOXG1-like presentation. Using trio-based exome sequencing, we identified a homozygous missense mutation in the Transducin-like enhancer of split-1 (TLE1) gene, encoding for a non DNA-binding transcriptional corepressor, highly expressed in the postnatal brain. The regulation of the post-mitotic neural survival activity of TLE1 depends critically on an interaction with FOXG1, a gene shown to be involved in a postnatal microcephaly syndrome. Functional analysis on affected dermal fibroblasts showed a significant decrease in mitotic and proliferative index, indicating a lengthening of the cell cycle and a delay in mitosis, supporting that this gene could be a new candidate for postnatal microcephaly.
产后小头畸形包括一组严重程度各异的神经发育障碍，其特征是出生时头围正常，随后产后头围减速超过均值以下3个标准差（SD）。许多产后小头畸形综合征是由已知对发育中的前脑基因表达调控很重要的基因突变引起的。我们研究了一个患有产后小头畸形、口面部运动障碍、痉挛性四肢瘫痪的巴基斯坦近亲家庭，磁共振成像（MRI）显示有皮质萎缩伴髓鞘形成延迟，提示类似FOXG1相关的表现。通过基于三联体的外显子组测序，我们在分裂抑制因子样增强子1（TLE1）基因中鉴定出一个纯合错义突变，该基因编码一种非DNA结合转录共抑制因子，在产后大脑中高度表达。TLE1的有丝分裂后神经存活活性的调节关键取决于与FOXG1的相互作用，FOXG1是一个已被证明与一种产后小头畸形综合征有关的基因。对受影响的皮肤成纤维细胞进行的功能分析显示，有丝分裂和增殖指数显著降低，表明细胞周期延长和有丝分裂延迟，支持该基因可能是产后小头畸形的一个新候选基因。
