Immunofluorescence staining of HeLa cells with overexpressed wild-type human PURA (yellow). Image credit: Proske et al. (CC BY 4.0)
PURA syndrome is a neurodevelopmental disorder that affects about 650 patients worldwide, resulting in a range of symptoms including neurodevelopmental delays, intellectual disability, muscle weakness, seizures, and eating difficulties.
The condition is caused by a mutated gene that codes for a protein called PURA. PURA binds RNA – the molecule that carries genetic information so it can be translated into proteins – and has roles in regulating the production of new proteins. Contrary to other conditions that result from mutations in a single gene, PURA syndrome patients show ‘high penetrance’, meaning almost every reported mutation in the gene leads to symptoms.
Proske, Janowski et al. wanted to understand the molecular basis for this high penetrance. To find out more, the researchers first examined how patient mutations affected the location of the PURA in the cell, using human cells grown in the laboratory. Normally, PURA travels to P-bodies, which are groupings of RNA and proteins involved in regulating which genes get translated into proteins. The researchers found that in cells carrying PURA syndrome mutations, PURA failed to move adequately to P-bodies.
To find out how this ‘mislocalization’ might happen, Proske, Janowski et al. tested how different mutations affected the three-dimensional folding of PURA. These analyses showed that the mutations impair the protein’s folding and thereby disrupt PURA’s ability to bind RNA, which may explain why mutant PURA cannot localize correctly.
Proske, Janowski et al. describe the molecular abnormalities of PURA underlying this disorder and show how molecular analysis of patient mutations can reveal the mechanisms of a disease at the cell level. The results show that the impact of mutations on the structural integrity of the protein, which affects its ability to bind RNA, are likely key to the symptoms of the syndrome. Additionally, their approach used establishes a way to predict and test mutations that will cause PURA syndrome. This may help to develop diagnostic tools for this condition.
