Revisiting the phenotype associated with FOXG1 mutations:Two novel cases of congenital Rett variant
ABSTRACT 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.
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- "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
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- "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
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- "The most intensively investigated early vocalization type is crying, which has been discussed – if it does not decline with growing age – as a marker for later deviations such as aggressive behavior, eating and sleeping difficulties, hyperactivity or even severe developmental disorders such as autism spectrum disorders or Rett syndrome (Bahi-Buisson et al., 2010; Esposito & Venuti, 2010; Forsyth & Canny, 1991; Papousek & Von Hofacker, 1998; Papousek, Wurmser, & von Hofacker, 2001; Von Kries, Kalies, & Papousek, 2006; Wolke, Rizzo, & Woods, 2002). Apart from crying, characteristics of canonical babbling that should emerge by no later than 10 months of age have been discussed as indicators for developmental disabilities (Nathani, Oller, & Neal, 2007; Oller, 1995; Oller, Eilers, Neal, & Schwartz, 1999): children with Rett syndrome, Down syndrome, Williams syndrome, cerebral palsy or profound hearing impairment were reported to enter the babbling-stage with a significant delay (Levin, 1999; Lynch et al., 1995; Marschik et al., 2011b; Masataka, 2001; Nathani et al., 2007; Tams- Little & Holdgrafer, 1998). "
ABSTRACT: To assess whether there are qualitatively deviant characteristics in the early vocalizations of children with Rett syndrome, we had 400 native Austrian-German speakers listen to audio recordings of vocalizations from typically developing girls and girls with Rett syndrome. The audio recordings were rated as (a) inconspicuous, (b) conspicuous or (c) not able to decide between (a) and (b). The results showed that participants were accurate in differentiating the vocalizations of typically developing children compared to children with Rett syndrome. However, the accuracy for rating verbal behaviors was dependent on the type of vocalization with greater accuracy for canonical babbling compared to cooing vocalizations. The results suggest a potential role for the use of rating child vocalizations for early detection of Rett syndrome. This is important because clinical criteria related to speech and language development remain important for early identification of Rett syndrome.Research in developmental disabilities 11/2011; 33(2):461-6. DOI:10.1016/j.ridd.2011.10.007 · 4.41 Impact Factor