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

Abstract

AbstractBackgroundPatients 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.