Abnormal expression of GABA receptor subunits and hypomotility upon loss of in zebrafish.

We used whole-exome sequencing (WES) to determine the genetic etiology of a patient with a multi-system disorder characterized by a seizure phenotype. WES identified a heterozygous missense mutation in the gene (c.875C>T). encodes the alpha subunit of the gamma-aminobutyric acid receptor A (GABAR). The GABAR is a ligand gated ion channel that mediates the fast inhibitory signals of the nervous system, and mutations in the subunits that compose the GABAR have been previously associated with human disease. To understand the mechanisms by which regulates brain development, we developed a zebrafish model of deficiency. expression is restricted to the nervous system and behavioral analysis of morpholino injected larvae suggests that the knockdown of results in hypoactivity and defects in the expression of other subunits of the GABAR. Expression of the human GABRA1 protein in morphants partially restored the hypomotility phenotype. In contrast, the expression of the c.875C>T variant did not restore these behavioral deficits. Collectively, these results represent a functional approach to understand the mechanisms by which loss-of-function alleles cause disease.