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Alternative RNA Splicing02:18

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Dong Li1,2,3, Qin Wang4, Allan Bayat5,6,7

  • 1Center for Applied Genomics, and.

The Journal of Clinical Investigation
|November 14, 2023
PubMed
Summary
This summary is machine-generated.

Pathogenic variants in three splicing factors, U2AF2, PRPF19, and RBFOX1, cause neurodevelopmental disorders (NDDs). This study reveals a genetic network critical for human brain development and function.

Keywords:
DevelopmentGenetic diseasesGeneticsNeurodevelopmentiPS cells

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Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • Pre-mRNA splicing is crucial for neurological function, but its role in neurodevelopmental disorders (NDDs) is not fully understood.
  • Dysregulation of splicing machinery is increasingly linked to neurological deficits.

Purpose of the Study:

  • To investigate the role of spliceosome subunits in NDDs.
  • To identify genetic variants in splicing factors associated with NDDs.
  • To elucidate the molecular mechanisms underlying splicing factor dysfunction in brain development.

Main Methods:

  • Identification and characterization of de novo variants in U2AF2 and PRPF19 in individuals with NDDs.
  • Functional assays using model substrates and human pluripotent stem cell-derived neurons.
  • Utilizing Drosophila melanogaster models to assess the impact of orthologous gene variants on neural development and behavior.
  • Transcriptome profiling and reanalysis of clinical exome data.

Main Results:

  • Identified numerous de novo missense variants in U2AF2 and PRPF19 associated with NDDs.
  • Demonstrated that U2AF2 variants impair splicing and reduce neuritogenesis in human neurons.
  • Drosophila models with loss of function in U2af50 and Prp19 exhibited lethality, abnormal brain patterning, and social deficits.
  • Identified RBFOX1 as a third NDD-causative splicing factor, with identified variants showing loss of function.

Conclusions:

  • U2AF2, PRPF19, and RBFOX1 are implicated as novel NDD-causative genes.
  • These findings establish a genetic network with a hierarchical structure essential for human brain development.
  • The study highlights the critical role of pre-mRNA splicing in neurodevelopment.