Non-Potluck Post: Finding the RING in neurodevelopment

In a recent study published to the PNAS, Pierce and colleagues examines the consequences of a mutation to RING1, a protein coding gene that plays a role in  “epigenetic regulation of gene expression” during neurodevelopment, in a case study of a 13-year-old girl with who displays neurodevelopmental, psychiatric, and physical abnormalities (p. 1558).From genomic DNA comparison between the patient and her parents found the mutation was absent in both of the parents as well in a larger comparative sample of >120,000 exomes from a public database. Due to the lack of finding the a mutation of RING1 p.R95Q in both the parents and the database sample the authors identified mutation as a de novo mutation.

Once the authors identified the location of the mutation they compared the mutated RING1 p.R95Q to a wild type of RING1. RING1 in a non-abnormal in individual ubiquitylate histone H2A (e.g. it attaches ubiquitin which is a small protein to a targeted protein, in this case histone H2A). However, in the patient the researchers found RING1 p.R95Q failed to attach the protein together leading them to suggest the neurodevelopmental disorders the patient exhibited was caused by this mutation.

"RING 1 p.R95Q causes a defect in ubiquitylation of histone H2A specifically on nucleosomes. (A) In vitro nucleosome ubiquitylation assay of wild-type RING1 or RING1 p.R95Q heterodimers with BMI1 or PCGF1. All proteins and nucleosomes were expressed and purified, and protein concentrations in samples were matched using UV absorbance at 280 nm. Histone H2A was detected by immunoblotting. The RING1 p.R95Q mutant is deficient at ubiquitylating H2A in nucleosomes. (B) Structure of the RING2/BMI1 complex, showing BMI1 (tan), RING2 (green), and E2 (gold) bound to a nucleosome (gray) (PDB ID code 4R8P). The structure highlights the contact between the conserved positive arginine residue (blue spheres) and the nucleosome acidic patch (shown in red)." Pierce et al., 2017

The importance of this paper allowed for researchers to get “a glimpse into the role of RING1 in human neuronal development” and the impact it has on causing psychological disorders (p. 1562).

There was a lot more to this paper, however, I am not familiar enough with what was done to explain what they did in my own words.  

The paper can be read here.