Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations
| Autor: | Aysegul O. Gezer, Behirda Karaj, Vincent Shaw, Huijie Feng, Richard R. Neubig, Benita Sjögren |
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| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | Neurology. 89:762-770 |
| ISSN: | 1526-632X 0028-3878 |
| DOI: | 10.1212/wnl.0000000000004262 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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