Characterizing fatty acid oxidation genes in Drosophila

Abstract

In this study, we leverage the power and tractability of Drosophila genetics to better understand the molecular mechanisms underlying a group of rare genetic diseases known as fatty acid oxidation disorders. We use CRISPR-Cas9 to generate mutations in 6 putative fatty acid oxidation genes in Drosophila, then analyze the phenotypes and acylcarnitine profiles of these flies. We find that while Arc42 and CG4860 are both predicted orthologs of human ACADS, only Arc42 loss of function mirrors the acylcarnitine profile of ACADS loss of function. Acylcarnitine profiles also support our previous identification of Mcad as the likely ACADM ortholog, and reveal the deleterious effects of a single codon deletion in Mtpα (the predicted human HADHA ortholog). Finally, we observe that loss of function in Etf-QO and in CG7834-predicted orthologs of human ETFDH and ETFB, respectively-is homozygous lethal in flies. Producing animal models like these will enable new approaches to studying fatty acid oxidation disease progression, symptomatic variability, and therapeutic intervention.

Keywords: Arc42; CG4860; CG7834/Etfb; Drosophila; Etf-QO; Mcad; Mtpα; CRISPR-Cas9; electron transfer; fatty acid oxidation; inborn errors of metabolism; β-oxidation.