Paper

A Point Mutation in the RNA Recognition Motif of CSTF2 Associated with Intellectual Disability in Humans Causes Defects in 3' End Processing

Macdonald, Clinton C, Billuart, Pierre, Grozdanov, Petar N, Latham, Michael P, Kalscheuer, Vera M, Masoumzadeh, Elahe, Marie-Ange Delrue, Bienvenu, Thierry

2020

Overview

CSTF2 encodes an RNA-binding protein that is essential for mRNA cleavage and polyadenylation (C/P). No disease-associated mutations have been described for this gene. Here, we report a mutation in the RNA recognition motif (RRM) of CSTF2 that changes an aspartic acid at position 50 to alanine (p.D50A), resulting in intellectual disability in male patients. In mice, this mutation was sufficient to alter polyadenylation sites in over 1,000 genes critical for brain development. Using a reporter gene assay, we demonstrated that C/P efficiency of CSTF2D50A was lower than wild type. To account for this, we determined that p.D50A changed locations of amino acid side chains altering RNA binding sites in the RRM. The changes modified the electrostatic potential of the RRM leading to a greater affinity for RNA. These results highlight the importance of 3' end mRNA processing in expression of genes important for brain plasticity and neuronal development.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Alanine / Amino acids / Aspartic acid / Binding sites / Developmental plasticity / Electrostatic properties / Gene expression / Genes / Intellectual disabilities / Molecular Biology / mRNA / mRNA processing / Mutation / Point mutation / Polyadenylation / Reporter gene / RNA processing / RNA-binding protein