Abstract
Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.
Highlights
IntroductionForkhead Box G1 (FOXG1) syndrome (OMIM #613454) is a rare and severe neurodevelopmental disorder caused by heterozygous de novo mutations in the gene encoding the transcription factor
FOXG1 syndrome (OMIM #613454) is a rare and severe neurodevelopmental disorder caused by heterozygous de novo mutations in the gene encoding the transcription factorForkhead Box G1 (FOXG1)
FOXG1 syndrome is associated with autism spectrum disorders (ASD) and FOXG1 variants are identified in patients with ASD [6]
Summary
FOXG1 syndrome (OMIM #613454) is a rare and severe neurodevelopmental disorder caused by heterozygous de novo mutations in the gene encoding the transcription factor. FOXG1 has fundamental and non-redundant roles in brain development, from the timing of neurogenesis to the patterning of the cerebral cortex [1,2] It has been previously classified as a congenital variant of Rett syndrome The most severe phenotypes occur in patients with frameshift or nonsense mutations in the N-terminal domain, including the Forkhead domain, while milder phenotypes associate with FOXG1 missense mutations in the Forkhead domain [5]. As this genetic variability in patients makes it difficult to pinpoint the direct and indirect outcomes of identified mutations in the FOXG1 gene, the challenge remains to dissect genotype–phenotype associations. FOXG1 syndrome, and explore up-to-date disease models, aiming to advance potential therapeutic avenues
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