Revisiting the phenotype associated with FOXG1 mutations:Two novel cases of congenital Rett variant
Université Paris Descartes, Institut Cochin, CNRS (UMR8104), Paris, France.Neurogenetics (Impact Factor: 2.88). 10/2009; 11(2):241-9. DOI: 10.1007/s10048-009-0220-2
The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo mutations (c.1248C>G, p.Y416X and c.460_461dupG, p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.
[Show abstract] [Hide abstract]
- "with absent speech, variable epilepsy, corpus callosum abnormalities , generalized hypotonia, and choreiform movements [Bisgaard et al., 2006; Ariani et al., 2008; Papa et al., 2008; Jacob et al., 2009; Bahi-Buisson et al., 2010; Mencarelli et al., 2010; Philippe et al., 2010; Kort€ um et al., 2011; Le Guen et al., 2011; Seltzer et al., 2014]. "
ABSTRACT: FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T > G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders. © 2015 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37353 · 2.16 Impact Factor
[Show abstract] [Hide abstract]
- "Reinforcing the likely maladaptive function of altered levels of FOXG1, deletions and missense mutations in this gene have been associated with an atypical Rett syndrome and small brain size (Ariani et al., 2008; Bahi-Buisson et al., 2010; Mencarelli et al., 2010). This is interesting, as it suggests that deviations in FOXG1 levels during brain development, in excess and defects, cause opposite modulation in brain growth but a similarly disabling outcome, characterized by intellectual disability and ASD-like symptoms. "
ABSTRACT: Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD. Copyright © 2015 Elsevier Inc. All rights reserved.Cell 07/2015; 162(2):375-390. DOI:10.1016/j.cell.2015.06.034 · 32.24 Impact Factor
[Show abstract] [Hide abstract]
- "Several recent studies have shown that mutation in the gene encoding FoxG1, a member of the forkhead family of transcription factors, also causes Rett syndrome (Bahi-Buisson et al., 2010; Jacob et al., 2009; Le Guen et al., 2010; Mencarelli et al., 2009; Philippe et al., 2009). Although studied extensively in the context of brain development where it plays a critical role in regulating the proliferation of neural progenitor cells (Tao and Lai, 1992; Xuan et al., 1995; Hanashima et al., 2004; Hanashima et al., 2002), the physiological significance of FoxG1 in the mature brain is poorly understood. "
ABSTRACT: The methyl-CpG binding protein 2 (MeCP2) is a widely expressed protein, the mutations of which cause Rett syndrome. The level of MeCP2 is highest in the brain where it is expressed selectively in mature neurons. Its functions in postmitotic neurons are not known. The MeCP2 gene is alternatively spliced to generate two proteins with different N termini, designated as MeCP2-e1 and MeCP2-e2. The physiological significance of these two isoforms has not been elucidated, and it is generally assumed they are functionally equivalent. We report that in cultured cerebellar granule neurons induced to die by low potassium treatment and in Aβ-treated cortical neurons, Mecp2-e2 expression is upregulated whereas expression of the Mecp2-e1 isoform is downregulated. Knockdown of Mecp2-e2 protects neurons from death, whereas knockdown of the e1 isoform has no effect. Forced expression of MeCP2-e2, but not MeCP2-e1, promotes apoptosis in otherwise healthy neurons. We find that MeCP2-e2 interacts with the forkhead protein FoxG1, mutations of which also cause Rett syndrome. FoxG1 has been shown to promote neuronal survival and its downregulation leads to neuronal death. We find that elevated FoxG1 expression inhibits MeCP2-e2 neurotoxicity. MeCP2-e2 neurotoxicity is also inhibited by IGF-1, which prevents the neuronal death-associated downregulation of FoxG1 expression, and by Akt, the activation of which is necessary for FoxG1-mediated neuroprotection. Finally, MeCP2-e2 neurotoxicity is enhanced if FoxG1 expression is suppressed or in neurons cultured from FoxG1-haplodeficient mice. Our results indicate that Mecp2-e2 promotes neuronal death and that this activity is normally inhibited by FoxG1. Reduced FoxG1 expression frees MecP2-e2 to promote neuronal death.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(8):2846-55. DOI:10.1523/JNEUROSCI.5841-11.2012 · 6.34 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.