GNAO1 Mutations Affecting the N‐Terminal α‐Helix of Gαo Lead to Parkinsonism

Abstract

BackgroundPatients carrying pathogenic variants in GNAO1 present a phenotypic spectrum ranging from severe early‐onset epileptic encephalopathy and developmental delay to mild adolescent/adult‐onset dystonia. Genotype–phenotype correlation and molecular mechanisms underlying the disease remain understudied.MethodsWe analyzed the clinical course of a child carrying the novel GNAO1 mutation c.38T>C;p.Leu13Pro, and structural, biochemical, and cellular properties of the corresponding mutant Gαo—GNAO1‐encoded protein—alongside the related mutation c.68T>C;p.Leu23Pro.ResultsThe main clinical feature was parkinsonism with bradykinesia and rigidity, unlike the hyperkinetic movement disorder commonly associated with GNAO1 mutations. The Leu ➔ Pro substitutions have no impact on enzymatic activity or overall folding of Gαo but uniquely destabilize the N‐terminal α‐helix, blocking formation of the heterotrimeric G‐protein and disabling activation by G‐protein‐coupled receptors.ConclusionsOur study defines a parkinsonism phenotype within the spectrum of GNAO1 disorders and suggests a genotype–phenotype correlation by GNAO1 mutations targeting the N‐terminal α‐helix of Gαo. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies

“…While the study by Knight et al does not address the genotype-phenotype correlation of GNAO1 mutations ( 52 ), Dominguez-Carral et al identified Gβγ binding as the best predictor for clinical severity ( 51 ). Although we also found a correlation for the defects in Gβγ interaction, we conclude that it cannot serve as an efficient predictor of disease severity, and in fact loss of heterotrimer formation completely fails to agree with severe clinical manifestations in some cases ( 50 ). In our work, we tested such characteristics of pathogenic Gαo variants as (i) expression levels, (ii) ability to bind and hydrolyze guanine nucleotides, (iii) intracellular localization, (iv) binding to physiological interaction partners (RGS19 and Gβγ), (v) GPCR coupling, and (vi) neomorphic interactions with Ric8A and Ric8B proteins.…”

“…Accordingly, the C215Y variant, as the T241_N242insPQ (c.724–8G > A) mutant recently characterized by us ( 49 ), falls into the milder end of the spectrum of GNAO1 encephalopathy with adolescent/adult onset ( 19 ). Along the same line, we recently showed that 2 GNAO1 mutations affecting the N-terminus of Gαo — L13P and L23P — lose Gβγ binding without acquiring the neomorphic Ric8 interaction, in agreement with their association with a mild parkinsonism phenotype ( 50 ).…”