Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities...

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• De novo mutations in U2AF2 are linked to developmental delays and intellectual disabilities.
• The precise molecular mechanisms underlying these neurodevelopmental disorders remain unclear.

Purpose of the Study:

• To investigate how specific U2AF2 mutations affect its RNA binding affinity and function.
• To elucidate the molecular basis of U2AF2-associated neurodevelopmental disorders.

Main Methods:

• Fluorescence anisotropy RNA binding assays were used to measure U2AF2 mutant binding affinity.
• Crystal structures of U2AF2 mutants were determined at 1.4 Å resolution.
• Reanalysis of RNA sequencing data from U2AF2-depleted cells was performed.

Main Results:

• Recurrent U2AF2 missense mutants (Arg149Trp, Arg150His, Arg150Cys) showed reduced binding affinity for consensus splice site RNA.
• Crystal structures revealed that Arg149Trp and Arg150His mutations disrupt crucial hydrogen bonds with RNA.
• U2AF2 depletion altered splicing patterns of transcripts encoding RNA binding proteins (RBPs).

Conclusions:

• Impaired RNA interactions of U2AF2 variants contribute to neurodevelopmental disorders.
• Dysregulation of RBP-governed alternative splicing programs is implicated in these conditions.