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Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction by Dandan Wang; Maria Dao; Brian S Muntean; Andrew C Giles; Kirill A Martemyanov; Brock Grill is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## Abstract __GNAO1__ encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous __GNAO1__ mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate __C. elegans__ as a whole-animal behavioral model to study the functional effects of __GNAO1__ disorder-associated mutations. We tested several pathological __GNAO1__ mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression __in vivo__. We report that all three mutations tested (__G42R__, __G203R__ and __R209C__) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of __GNAO1 G42R__, which impaired numerous motor behaviors. Thus, __GNAO1__ pathological mutations result in conserved functional outcomes across animal models. Our study further establ

Who reads Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction?

Author

Dandan Wang; Maria Dao; Brian S Muntean; Andrew C Giles; Kirill A Martemyanov; Brock Grill

Published

2021

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)