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Eur J Med Genet. 2018 Dec;61(12):729-732. doi: 10.1016/j.ejmg.2018.05.002. Epub 2018 May 25.

TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly.

Author information

1
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. Electronic address: mara.cavallin@institutimagine.org.
2
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.
3
Pediatric Neurology APHP- Necker Enfants Malades University Hospital, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares", APHP- Necker Enfants Malades University Hospital, Paris, France.
4
Pediatric Radiology APHP- Necker Enfants Malades University Hospital, Paris, France; Image- Institut Imagine, INSERM UMR1163, Paris Descartes University, Hôpital Necker Enfants Malades, Paris, France.
5
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of inherited kidney diseases, INSERM UMR1163, Imagine Institute, Paris, France; Paris Diderot University, 75013, Paris, France.
6
Bioinformatic Core Facility, INSERM UMR1163, Imagine Institute, Paris, France.
7
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Genetics and development of the cerebral cortex, Institut Imagine, Paris, France. Electronic address: amandine.bery@inserm.fr.
8
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; Centre de Référence "Déficiences intellectuelles de causes rares", APHP- Necker Enfants Malades University Hospital, Paris, France; Genetics and development of the cerebral cortex, Institut Imagine, Paris, France. Electronic address: nadia.bahi-buisson@nck.aphp.fr.

Abstract

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.

KEYWORDS:

Cortical malformation; Postnatal microcephaly; TLE1

PMID:
29758293
DOI:
10.1016/j.ejmg.2018.05.002
[Indexed for MEDLINE]

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