GNAO1 mutations: from excessive movement to unexpected rigidity
GNAO1 disorders are rare but severe genetic diseases for which there are no well-established treatments. These disorders result from mutations in the most abundant G protein of the brain, Gαo, a protein responsible for transmitting signals from the outside to the inside of a cell.
The discovery of unexpected parkinsonism-like symptoms…
While all known GNAO1 patients suffer from hyperkinetic movement disorders (e.g. disorganized, uncontrolled movement), the researchers from the laboratory of Prof. Vladimir Katanaev in collaboration with clinicians from the Department of Pediatrics from the University Hospital of Cologne observed the opposite hypokinetic symptoms in a young patient, i.e. rigidity and difficulty in moving.
… explained by mutations with a unique location
Intrigued by these different clinical symptoms, they investigated the structural, biochemical, and cellular properties of the corresponding mutant Gαo proteins. The research teams found that the two mutations involved do not affect enzymatic activity or overall shape of Gαo, but uniquely destabilize a specific part of the protein, the N-terminal α-helix (shown in pink in the Figure below), preventing its normal interaction with its two other subunits and disabling signal transmission by G-protein-coupled receptors.
Novel mutations (in blue) affect the N-terminal α-helix (αN, in light pink) of Gαo, in contrast to all other mutations reported to date (in red), and prevent Gαo from interacting with its other subunits (transparent). © Adapted from Figure 1 in Solis et al. 2024.
These findings represent a significant step forward in understanding the complexity of GNAO1 disorders. By defining parkinsonism-like symptoms within the spectrum of GNAO1 disorders and revealing the molecular mechanisms of the mutations involved, the study provides important information for clinicians and researchers working to combat this rare genetic condition.