Metabolic changes underlying 16p11.2 deletion syndrome

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Modified Project Summary/Abstract Section PROJECT SUMMARY FAM57B is an autism risk gene, and part of the 16p11.2 disease locus. 16pdel syndrome is a severe and prevalent (1:2000 people) haploinsufficient disorder, caused by deletion of ~600 kb of chromosome 16. This syndrome is tightly associated with autism, language and intellectual disability, seizures, ADHD, hypotonia and obesity, however genetic contributions to each symptom are unclear. Our proposal addresses the novel hypothesis that alteration of FAM57B function is associated with autism and 16pdel syndrome, by changing cellular lipids of the ceramide pathway. Lipid cohort alteration may change neuronal plasma membrane composition and associated proteins, so altering synaptic activity and contributing to 16pdel symptoms. We defined a 16p11.2 functional interactome, and identified FAM57B as a pivotal ‘hub’ gene (McCammon et al. 2017). FAM57B has been additionally identified as an autism risk gene (Satterstrom et al. 2019). FAM57B contains a TLC domain found in ceramide synthase enzymes (CerS), but residues required for CerS activity are absent. Loss of function of fam57b in the zebrafish model led to significant changes in brain lipid species. Strikingly, we also observed altered plasma membrane architecture, mis-localization of synaptic proteins, depressed movement and decreased brain activity. The Aim will determine the role of FAM57B in ceramide synthesis and its impact on neuronal and brain function. We hypothesize that FAM57B regulates ceramide levels by interacting with CerS. We further hypothesize that FAM57B maintains the synaptic lipid and protein cohort contributing to neurotransmitter exocytosis. We will determine activity of FAM57B human and zebrafish homologues; delineate molecular changes at the neuronal synapse after loss of FAM57B and determine activity of fam567b in the zebrafish brain. This Aim will solve the function of FAM57B, giving insight into mechanisms underlying autism and 16pdel syndrome phenotypes.