Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations
- Resource Type
- Authors
- Aysegul O. Gezer; Behirda Karaj; Vincent Shaw; Huijie Feng; Richard R. Neubig; Benita Sjögren
- Source
- Neurology. 89:762-770
- Subject
- Male
0301 basic medicine
medicine.medical_specialty
Movement disorders
Adolescent
Encephalopathy
Mutagenesis (molecular biology technique)
GTP-Binding Protein alpha Subunits, Gi-Go
Biology
Blotting, Far-Western
Transfection
medicine.disease_cause
GNAO1
Article
03 medical and health sciences
Epilepsy
chemistry.chemical_compound
0302 clinical medicine
Receptors, Adrenergic, alpha-2
Internal medicine
Cyclic AMP
medicine
Humans
Cyclic adenosine monophosphate
Child
Genetic Association Studies
Loss function
Brain Diseases
Mutation
Dyskinesias
Movement Disorders
Infant
medicine.disease
HEK293 Cells
030104 developmental biology
Endocrinology
chemistry
Child, Preschool
Gain of Function Mutation
Female
Neurology (clinical)
medicine.symptom
030217 neurology & neurosurgery
- Language
- ISSN
- 1526-632X
0028-3878
Objective:To define molecular mechanisms underlying the clinical spectrum of epilepsy and movement disorder in individuals with de novo mutations in the GNAO1 gene.Methods:We identified all GNAO1 mutations reported in individuals with epilepsy (early infantile epileptiform encephalopathy 17) or movement disorders through April 2016; 15 de novo mutant alleles from 25 individuals were introduced into the Gαo subunit by site-directed mutagenesis in a mammalian expression plasmid. We assessed protein expression and function in vitro in HEK-293T cells by Western blot and determined functional Gαo-dependent cyclic adenosine monophosphate (cAMP) inhibition with a coexpressed α2A adrenergic receptor.Results:Of the 15 clinical GNAO1 mutations studied, 9 show reduced expression and loss of function (LOF; 50 values for α2A adrenergic receptor–mediated inhibition of cAMP. The GNAO1 LOF mutations are associated with epileptic encephalopathy while GOF mutants (such as G42R, G203R, and E246K) or normally functioning mutants (R209) were found in patients with movement disorders with or without seizures.Conclusions:Both LOF and GOF mutations in Gαo (encoded by GNAO1) are associated with neurologic pathophysiology. There appears to be a strong predictive correlation between the in vitro biochemical phenotype and the clinical pattern of epilepsy vs movement disorder.