Do Fragile X Syndrome and Other Intellectual Disorders Converge at Aberrant Pre-mRNA Splicing?

Shah, Sneha; Richter, Joel D.

doi:10.3389/fpsyt.2021.715346

Cited by 8 publications

(11 citation statements)

References 62 publications

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“…Finally, the dys-regulated splicing in Fragile X model mice may represent a point of convergence with other neurodevelopmental disorders [ 56 ]. For example, splicing is impaired in autism spectrum disorders [ 57 ], Rett Syndrome [ 58 ], Pten [ 59 ], and others [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm

Jung,

Shah,

Han

et al. 2023

PLoS Biol

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Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.

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Section: Discussionmentioning

confidence: 99%

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm

Jung,

Shah,

Han

et al. 2023

PLoS Biol

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“…The copyright holder has placed this this version posted August 3, 2022. ; https://doi.org/10.1101/2022.08.02.502495 doi: bioRxiv preprint 30 Finally, the dys-regulated splicing in Fragile X model mice may represent a point of convergence with other neurodevelopmental disorders (Shah and Richter 2021). For example, splicing is impaired in autism spectrum disorders (Irimia et al 2014), Rett Syndrome (Li et al 2016), Pten (Thacker et al 2020), and others (Shah et al 2021). Whether mis-splicing in these disorders are related mechanistically is unclear, but they may involve several of the same factors (e.g., MBNL1, PTBP1).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the dys-regulated splicing in Fragile X model mice may represent a point of convergence with other neurodevelopmental disorders (Shah and Richter 2021). For example, splicing is impaired in autism spectrum disorders (Irimia et al 2014), Rett Syndrome (Li et al 2016), Pten (Thacker et al 2020), and others (Shah et al 2021). Whether mis-splicing in these disorders are related mechanistically is unclear, but they may involve several of the same factors (e.g., MBNL1, PTBP1).…”

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confidence: 99%

FMRP-Regulated Alternative Splicing is Multifactorial and Resembles Splicing Control by MBNL1

Jung

Shah

Richter

2022

Preprint

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The neurodevelopmental disorder Fragile X Syndrome (FXS) is often modeled in Fmr1 knockout mice, which results in the loss of the RNA binding protein FMRP. In the brain, FMRP stalls ribosomes on specific mRNAs including Setd2, whose encoded protein catalyzes the epigenetic mark H3K36me3. In the absence of FMRP, SETD2 levels are excessive, which alters the H3K36me3 landscape and secondarily, alternative pre-mRNA splicing. Here we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, hnRNPQ, PTPB1, and MBNL1. FMRP binds to Mbnl1 mRNA and regulates its translation. In Fmr1-depleted cells, Mbnl1 RNA itself is mis-spliced, which results in the loss of a nuclear localization signal (NLS)-containing exon that in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This re-distribution of MBNL1 isoforms in Fmr1-deficient cells likely results in splicing changes in other RNAs. Mbnl1 mis-spicing also occurs in human FXS post-mortem brain. These data link FMRP-dependant impaired translation of splicing factors, such as MBNL1, to altered self-splicing and subcellular localization of the Mbnl1 RNA and protein. Altered expression of splicing factors in the absence of FMRP may cascade into the global dys-regulation of tissue specific splicing observed in Fmr1 deficient cells.

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“…SNRPC is a spliceosome component involved in 5' splice-site recognition, so it may affect the splicing of many different targets and could constitute a shared mechanism of splicing dysregulation of patients with RTT-spectrum phenotypes. The dysregulation of splicing factors and regulators has been described in RTT as well as in other monogenic intellectual disabilities and in autism spectrum disorder (ASD) [143]. The biological pathways affected by these splicing defects (neuronal development, vesicular activity, and cytoskeleton organisation) are also shared, which could suggest common pathomechanisms behind these disorders [143].…”

Section: Patients With Rtt Versus Patients With Rtt-like Phenotypesmentioning

confidence: 99%

“…The dysregulation of splicing factors and regulators has been described in RTT as well as in other monogenic intellectual disabilities and in autism spectrum disorder (ASD) [143]. The biological pathways affected by these splicing defects (neuronal development, vesicular activity, and cytoskeleton organisation) are also shared, which could suggest common pathomechanisms behind these disorders [143].…”

Section: Patients With Rtt Versus Patients With Rtt-like Phenotypesmentioning

confidence: 99%

Identification of molecular signatures and pathways involved in Rett syndrome using a multi-omics approach

Pascual‐Alonso

Xiol

Smirnov

et al. 2023

Preprint

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Background Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). MeCP2 is a multifunctional protein involved in many cellular processes, but the mechanisms by which its dysfunction causes disease are not fully understood. The duplication of MECP2 is the cause of a different disorder, MECP2 duplication syndrome (MDS), indicating that its dosage must be tightly regulated for proper cellular function. Moreover, there are patients with a remarkable phenotypic overlap with RTT and mutations in genes other than MECP2 (RTT-like), suggesting they could be involved in similar cellular functions. The purpose of this study was to characterize the molecular alterations in patients with RTT in order to identify potential biomarkers or therapeutic targets for this disorder. Methods We used a combination of transcriptomics (RNAseq) and proteomics (TMT-mass spectrometry) to characterize the expression patterns in fibroblast cell lines from 22 patients with RTT and detected mutation in MECP2, 15 patients with MDS, 12 patients with RTT-like phenotypes and 13 healthy controls. Transcriptomics and proteomics data were used to identify differentially expressed genes both at RNA and protein levels, which were further inspected via enrichment and upstream regulator analyses and compared to find shared features in patients with RTT. Results We identified molecular alterations in cellular functions and pathways that may contribute to the disease phenotype in patients with RTT,such as deregulated cytoskeletal components, vesicular transport elements, ribosomal subunits and mRNA processsing machinery. We also compared RTT expression profiles with those of MDS seeking changes in opposite directions that could lead to the identification of MeCP2 direct targets. Some of the deregulated transcripts and proteins were consistently affected in patients with RTT-like phenotypes, revealing potentially relevant molecular processes in patients with overlapping traits and different genetic aetiology. Conclusions The integration of data in a multi-omic analysis has helped to interpret the molecular consequences of MECP2 dysfunction, contributing to the characterisation of the molecular landscape in patients with RTT. The comparison with MDS provides knowledge of MeCP2 direct targets, whilst the correlation with RTT-like phenotypes highlights processes potentially contributing to the pathomechanism leading these disorders.

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Do Fragile X Syndrome and Other Intellectual Disorders Converge at Aberrant Pre-mRNA Splicing?

Cited by 8 publications

References 62 publications

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm

FMRP-Regulated Alternative Splicing is Multifactorial and Resembles Splicing Control by MBNL1

Identification of molecular signatures and pathways involved in Rett syndrome using a multi-omics approach

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