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

Abstract

The GNAO1 gene codes for the most commonly expressed Gα protein in the central nervous system. De novo GNAO1 variants cause complex early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder manifestations, and sometimes with both manifestations in the same patient. G-protein coupled receptor (GPCR) signaling is among the best studied molecular interaction pathways in the human organism, which provides the input needed to quantitatively evaluate 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 and anticipating symptoms and treatment response for future patients. We show that apparently similar mutations in GNAO1 can lead to distinct phenotypes through distinct modulation of the incoming GPCR signal.

Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

“…Finally, we found that loss of Gαo in iMSNs was responsible for inducing dystonia-like features often observed GNAO1 patients ( Mihalek et al, 2017 ), which could be considered a part of hyperkinetic motor program constrained by this neuronal population ( Durieux et al, 2009 ). The selective involvement of Gαo supports a dominant role of iMSN circuitry in dystonia ( Berardelli et al, 1998 ), including observed alterations in electrophysiological properties of iMSNs in mouse models of dystonia ( Sciamanna et al, 2020 ).…”

“…In light of the elucidated role of Gαo in regulating signaling to cAMP and motor coordination, we next investigated the impact of several mutations in Gαo associated with GNAO1 encephalopathy ( Kelly et al, 2019 ; Mihalek et al, 2017 ) using our recently developed molecular deconvolution platform ( Masuho et al, 2018 ). Structural modeling showed that these mutations mapped to highly conserved motifs among the Gα protein family residing predominantly around the phosphate-binding loop (P loop), switch II, and switch III regions ( Figure 4A ), suggesting potential influence on Gαo activation ( Bosch et al, 2012 ) and its interaction with guanine nucleotides ( Nakamura et al, 2013 ).…”

“…Clinical features of this disease include delayed psychomotor development, intractable seizures, and hyperkinetic involuntary movements. To date, 26 unique pathogenic variants in Gαo have been reported ( Kelly et al, 2019 ; Mihalek et al, 2017 ). Knockin mouse models carrying orthologous mutations to clinical variants in Gαo recapitulate movement dysregulation phenotypes ( Feng et al, 2019 ; Larrivee et al, 2019 ).…”

Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

“…For GNAO1 encephalopathy, although tetrabenazine was demonstrated to be the most effective drug, emergency GPi-DBS was shown to be helpful for those patients with hyperkinetic exacerbations (9). Furthermore, dissection of phenotype-genotype correlation suggested that different GNAO1 mutations affect the G protein function for the signaling loop in distinct ways that implicated different treatment options (11). This suggested possible application of precision medicine for different GNAO1 variants identi ed in the patients.…”

“…Phenotypic diagnosis only has limitations as many symptoms may have more than one underlying etiology and any particular pathophysiology can result in a complex combination of symptoms (6). Genetic diagnosis allows a comprehensive understanding of the underlying pathophysiology and provides speci c treatment options (7)(8)(9)(10)(11)(12).…”