Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

Akol, Ipek; Gather, Fabian; Vogel, Tanja

doi:10.3390/ijms23020954

Cited by 9 publications

(15 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 Loss-of-function mutations in FOXG1 cause FOXG1 syndrome, a neurodevelopmental disorder characterized by microcephaly, seizures, autistic symptoms, disrupted sleep patterns, and severe speech deficits. 4,5 Although believed to be a variant form of Rett syndrome until about a decade ago, distinctive features of the disorder were identified, including much more pronounced motor and speech impairments along with marked microcephaly and corpus callosum agenesis, leading to its recognition in 2016 as a separate and distinct disorder. 60 Among the effects that FOXG1 deficiency has on brain development and function, is an imbalance in E/I circuitry, which likely contributes to some of the defining problems of the disorder, including seizures and autistic-like behavior.…”

Section: The Principalsmentioning

confidence: 99%

“…61 Individuals with FOXG1 gene duplications also display seizures, autistic symptoms, and cognitive impairments, although these are milder than displayed by patients with FOXG1 syndrome. 5,22,62 Interestingly, autistic features in FOXG1 duplication syndrome mice are also associated with an imbalance of E/I signals. 61 In iPSC-derived neural organoids from autism spectrum disorder (ASD) patients, elevated FOXG1 expression has been proposed to cause dysregulated proliferation/differentiation and an overproduction of GABAergic neurons.…”

Section: The Principalsmentioning

confidence: 99%

“…Cyclin-dependent kinase-like 5 (CDKL5) is a ubiquitously expressed serine-threonine (Ser/Thr) kinase, [1][2][3] FOXG1 is a transcription factor of the forkhead family expressed selectively in the forebrain, 4,5 and methyl-CpG binding protein-2 (MeCP2) is a ubiquitously expressed protein that regulates transcription and chromatin structure by binding to methylated DNA. [6][7][8] MeCP2 is primarily (albeit not exclusively) a nuclear protein, [9][10][11] whereas FOXG1 and CDKL5 localize to both the nucleus and cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

show abstract

Section: The Principalsmentioning

confidence: 99%

Section: The Principalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

show abstract

“…FOXG1 gene (OMIM 164874), located at 14q12, encodes the forkhead box protein G1, a conserved transcriptional repressor, that play a critical role in forebrain development, from the timing of neurogenesis, to the patterning of the cerebral cortex and callosal projections. FOXG1 gene truncating mutations (frameshift or nonsense) in the N-terminal domain and 14q12 microdeletions associate a severe phenotype, while FOXG1 gene missense mutations in the forkhead domain lead to milder phenotype (Kortum et al, 2011;Leombroni et al, 2018;Mitter et al, 2018;Hou et al, 2020;Akol et al, 2022).…”

Section: Foxg1 Syndromementioning

confidence: 99%

Genetic heterogeneity in corpus callosum agenesis

et al. 2022

View full text Add to dashboard Cite

The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres. Agenesis of the corpus callosum (ACC), complete or partial, is one of the most common cerebral malformations in humans with a reported incidence ranging between 1.8 per 10,000 livebirths to 230–600 per 10,000 in children and its presence is associated with neurodevelopmental disability. ACC may occur as an isolated anomaly or as a component of a complex disorder, caused by genetic changes, teratogenic exposures or vascular factors. Genetic causes are complex and include complete or partial chromosomal anomalies, autosomal dominant, autosomal recessive or X-linked monogenic disorders, which can be either de novo or inherited. The extreme genetic heterogeneity, illustrated by the large number of syndromes associated with ACC, highlight the underlying complexity of corpus callosum development. ACC is associated with a wide spectrum of clinical manifestations ranging from asymptomatic to neonatal death. The most common features are epilepsy, motor impairment and intellectual disability. The understanding of the genetic heterogeneity of ACC may be essential for the diagnosis, developing early intervention strategies, and informed family planning. This review summarizes our current understanding of the genetic heterogeneity in ACC and discusses latest discoveries.

show abstract

“…• Can show poor postnatal growth and feeding problems that call for G-tube; constipation; reflux 129 130 131…”

Section: Introduction To Autism and Gastrointestinal Symptomsmentioning

confidence: 99%

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders

Davidson,

Holingue,

Jimenez-Gomez

et al. 2023

Semin Neurol

View full text Add to dashboard Cite

Gastrointestinal symptoms are common in most forms of neurodevelopment disorders (NDDs) such as in autism spectrum disorders (ASD). The current patient-reported outcome measures with validated questionnaires used in the general population of children without NDDS cannot be used in the autistic individuals. We explore here the multifactorial pathophysiology of ASD and the role of genetics and the environment in this disease spectrum and focus instead on possible diagnostics that could provide future objective insight into the connection of the gut-brain-microbiome in this disease entity. We provide our own data from both humans and a zebrafish model of ASD called Phelan-McDermid Syndrome. We hope that this review highlights the gaps in our current knowledge on many of these profound NDDs and that it provides a future framework upon which clinicians and researchers can build and network with other interested multidisciplinary specialties.

show abstract

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

Cited by 9 publications

References 85 publications

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

Genetic heterogeneity in corpus callosum agenesis

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders

Contact Info

Product

Resources

About