Danielle Tomasello, Whitehead Institute for Biomedical Research
Conference: Human Genome Meeting, Seoul, South Korea
Abstract Title: FAM57B Ceramide Synthase, a Hub Gene within 16p11.2 Deletion Syndrome, Maintains Physiological Lipid Membrane Composition
Abstract: 16p11.2 deletion syndrome is a macrodeletion of a core of 25 genes that underlies a combination of severe neurodevelopmental and mental health disorders, including autism spectrum disorder, epilepsy, attention deficit hyperactivity disorder, macrocephaly, intellectual disability, and language deficits. Within these core genes, the ceramide synthase, encoded by fam57b, has emerged as a candidate gene from our previous findings indicating fam57b interacts with a large proportion of 16p11.2 interval genes. We sought out to determine the neuronal function of the largely uncharacterized FAM57B. Using fam57ba-/-;fam57bb-/- zebrafish larvae, we discovered disruption of integral membrane lipids by metabolite profiling of larvae brains. 16p11.2 deletion fibroblasts displayed a similar lipid metabolite profile, indicating FAM57B is a key component of lipid homeostasis. Live larvae brain electrophysiology indicated decreased extracellular action potentials and lack of burst activity in mutant larvae. Electrophysiological recordings correlated with significantly depressed behavioral responses to dark-stimulus startle and baseline as well as evoked movement to seizure-inducing drug pentylenetetrazol. Lipid raft disorganization in the brain was observed after ventricle injection of cholera-toxin subunit B in mutant larvae compared to wild-type. Lipid membrane disruption was further observed after surface protein isolation in the larvae brain indicated significant changes in protein abundance, illuminating underlying biochemical changes in plasma lipids that resulted in correlating behavioral, electrophysiological, morphological, and molecular deficits. Together, these studies uncover a previously unknown function for FAM57B to maintain lipid membrane homeostasis therein supporting neuronal function.