Background: Patients 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.
Methods: We 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.
Results: The 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.
Conclusions: Our 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.
Keywords: GNAO1; Gαo; G‐protein‐coupled receptors; hypokinetic phenotype; parkinsonism.
© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.