Molecular map of GNAO1-related disease phenotypes and reactions to therapy

Abstract

The GNAO1 gene codes for the most commonly expressed G protein in the central nervous system. Pathogenic GNAO1 variants result in early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder, and sometimes with both mani-festations in the same patient. The existing extensive knowledge about G-protein coupled receptor (GPCR) signaling provides the input needed to describe quantitatively how mutations modify the GPCR signal. This in turn allows rational interpretation of distinct phenotypes arising from mutations in GNAO1. In this work we outline a model that enables understanding of clinical phenotypes at a molecular level. The mutations affecting the catalytic pocket of GNAO1, we show, result in the improper withdrawal of the signal, and give rise to epileptic phenotypes (EPs). The converse is not true - some pure EPs are caused by mutations with no obvious impact on catalysis. Mutations close to the interface with GNAO1s downstream effector block the signal propagation in that direction, and manifest as a movement disorder phenotype without epilepsy. Quantifying the reported reaction to therapy highlights the tendency of the latter group to be unresponsive to the therapies currently in use. We argue, however, that the majority of clinically described mutations can impact several aspects of GNAO1 function at once, resulting in the continuum of phenotypes observed in patients. The reasoning based on GNAO1 signaling model provides a precision medicine paradigm to aid clinicians in selecting effective categories of medication, and in addition, can suggest pragmatic targets for future therapies.