Molecular Systems Biology of Neurodevelopmental Disorders, Rett Syndrome as an Archetype

Faúndez, Víctor; Wynne, Meghan E.; Crocker, Amanda; Tarquinio, Daniel

doi:10.3389/fnint.2019.00030

Cited by 13 publications

(8 citation statements)

References 170 publications

(197 reference statements)

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“…Rett syndrome is a neurodevelopmental disease without evidence of degeneration and thus rescuing MECP2 downstream activity might improve disease pathophysiology even in adulthood ( Faundez et al, 2019 ). In murine models, reintroduction of MECP2 to adult animals led to vast phenotypic improvements ( Guy et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Unterman¹,

Bloch²,

Cazacu

et al. 2021

eLife

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Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

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Section: Discussionmentioning

confidence: 99%

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Unterman¹,

Bloch²,

Cazacu

et al. 2021

eLife

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show abstract

“…Rett syndrome is a neurodevelopmental disease without evidence of degeneration and thus rescuing MECP2 downstream activity might improve disease pathophysiology even in adulthood (67) . In murine models, reintroduction of MECP2 to adult animals led to vast phenotypic improvements (13) .…”

Section: Discussionmentioning

confidence: 99%

Expanding theMECP2network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Unterman

Bloch

Cazacu³

et al. 2021

Preprint

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Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appear to act on Nuclear Factor Kappa B (NF-κB) signalling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

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“…On the surface, it appears logical to hypothesize that discrete genetic causes of neurodevelopmental disorders would provide relatively straightforward answers to questions about the underlying neuropathology. On the contrary, even in the case of monogenetic disorders, complex processes govern the downstream effects, as the loss of a single gene results in drastic effects on the activity of a multitude of other cellular processes [24,25].…”

Section: Introductionmentioning

confidence: 99%

FMR1 and Autism, an Intriguing Connection Revisited

Fyke

Velinov

2021

Genes

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Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy.

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Molecular Systems Biology of Neurodevelopmental Disorders, Rett Syndrome as an Archetype

Cited by 13 publications

References 170 publications

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Expanding theMECP2network using comparative genomics reveals potential therapeutic targets for Rett syndrome

FMR1 and Autism, an Intriguing Connection Revisited

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