UCLA

Episodic ataxias (EAs) are clinically and genetically heterogeneous conditions manifesting with intermittent and recurrent attacks of incoordination and imbalance triggered by stress and exertion. Advances in sequencing have led to the identification of an increasing number of genetic variants of unknown significance. EA6 was designated based on the discovery of a spontaneous heterozygous mutation in a child with EA in SLC1A3, which encodes a glial glutamate transporter, EAAT1. The focus of my thesis is twofold: to ascertain potential pathogenicity of two new genetic variants in SLC1A3, and to generate and validate transgenic fruit flies as a model organism for EA6. I present data demonstrating impaired glutamate uptake of the mutant transporters in expression studies in both mammalian and insect cell lines to support pathogenicity of the two genetic variants. Furthermore, I generated transgenic fruit flies that harbor the first human EA6 mutation and found the mutant fruit flies with markedly decreased survival, which could be used in future studies to screen for drug response and modifier genes.