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

• Published in: European journal of medical genetics Vol. 61; no. 12; pp. 729 - 732
• Main Authors: Cavallin, Mara, Maillard, Camille, Hully, Marie, Philbert, Marion, Boddaert, Nathalie, Reilly, Madeline Louise, Nitschké, Patrick, Bery, Amandine, Bahi-Buisson, Nadia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.12.2018; Elsevier
• Subjects: Brain - diagnostic imaging; Brain - pathology; Child; Child, Preschool; Cortical malformation; Female; Forkhead Transcription Factors - genetics; Genetic Predisposition to Disease; Humans; Infant; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Life Sciences; Magnetic Resonance Imaging; Male; Microcephaly - diagnostic imaging; Microcephaly - genetics; Microcephaly - pathology; Mutation; Nerve Tissue Proteins - genetics; Neurogenesis - genetics; Neurons and Cognition; Pedigree; Postnatal microcephaly; Repressor Proteins - genetics; TLE1; Whole Exome Sequencing; TLE1; Postnatal microcephaly; Cortical malformation
• ISSN: 1769-7212; 1878-0849; 1878-0849
• DOI: 10.1016/j.ejmg.2018.05.002

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.