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Scientific article
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English

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

Published inMovement disorders, mds.29720
Publication date2024-02-15
First online date2024-02-15
Abstract

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.

eng
Keywords
  • G-protein-coupled receptors
  • GNAO1
  • Gαo
  • Hypokinetic phenotype
  • Parkinsonism
Citation (ISO format)
SOLIS, Gonzalo et al. GNAO1 Mutations Affecting the N‐Terminal α‐Helix of Gαo Lead to Parkinsonism. In: Movement disorders, 2024, p. mds.29720. doi: 10.1002/mds.29720
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Identifiers
ISSN of the journal0885-3185
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