953A Poster - 15. Models of human disease
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Zelha Nil ^{1, 2}; Carlos Ferreira ³; Camilo Toro ⁴; David Adams ⁵; Oguz Kanca ^{1, 2}; Shinya Yamamoto ^{1, 2}; Hugo Bellen ^{1, 2}; Undiagnosed Diseases Network

Affiliations:
1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 2) Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA ; 3) Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 4) Adult NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 5) Human Biochemical Genetics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Keywords:
b. neural disorder; g. neurotransmitters

Glutaminase (GLS) encodes a mitochondrial enzyme that converts L-glutamine into L-glutamate in mitochondria. In addition to serving as building blocks of proteins, these amino acids have many additional roles in vivo including maintaining the cellular redox status, fueling the Krebs cycle, and synaptic transmission. Recent studies have identified rare human diseases that are caused by loss- (LOF) or gain-of-function (GOF) variants in GLS. Due to the pleiotropic roles of glutamine, glutamate and other related metabolites in diverse cellular processes, the precise molecular mechanisms underlying the human diseases are unknown. Here, we generated and characterized different alleles of fly GLS and transgenic human GLS expressing lines to study these disorders. We find that complete loss of GLS (GLS^Gal4ΔAll) or the loss of the isoforms with strong mitochondrial targeting signals (GLS^ΔMito) do not cause any obvious defects. However, a dominant negative allele expressing the short N-terminal fragments of different GLS isoforms (GLS^DN) shows decreased survival, shortened life-span, reduced body size, progressive loss of motor skills and glutamine accumulation similar to diseases caused by some GLS missense variants in humans. Moreover, we found that the ubiquitous overexpression of a potential GOF variant (p.Ser482Cys) in human GLS in wild-type flies is toxic, whereas overexpression of the reference or predicted LOF variants do not show any effect. These preliminary data argue that Drosophila is a promising model to explore molecular mechanisms of rare human GLS diseases.