Pesquisa e inovação biomédica avançada

FAM57B, a hub gene within 16p11.2 deletion syndrome, maintains physiological lipid membrane composition

Danielle L Tomasello, Jiyoon Kim, Jasmine M McCammon, Tony Futerman and Hazel Sive

The genetic basis for mental health disorders is complex, making diagnostics unreliable and personalized treatments complex. The present studies are aimed to address this challenge with a new approach to identify molecular changes in 16p11.2 deletion syndrome. In this prevalent syndrome (occurring in 1 in 2000 individuals) part of chromosome 16 is lost, encompassing a core of 25 genes. Deletion leads to severe brain symptoms including autism, intellectual disability and epilepsy. Within these core genes, the putative 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. The research team sought out to determine the neuronal function of the largely uncharacterized FAM57B. Using fam57ba-/-; fam57bb-/- mutant zebra fish larvae and discovered disruption of integral membrane lipids by metabolite profiling of larvae brains. Patient 16p11.2 deletion differentiated neurons displayed a similar lipid metabolite profile, suggesting FAM57B is a key component of lipid homeostasis. Lipid raft disorganization in the brain was observed after ventricle injection of cholera-toxin subunit B in mutant larvae compared to wildtype. Lipid membrane disruption was further observed after surface protein isolation in the larvae brain indicated significant changes in protein abundance. Live larvae brain electrophysiology indicated decreased extracellular action potentials and lack of burst activity in mutant larvae. Electrophysiological recordings correlated with significantly depressed behavioural responses to dark-stimulus startle and baseline as well as evoked movement to seizure-inducing drug pentylenetetrazol. Together a model whereby FAM57B functions to maintain normal plasma membrane physiology, necessary for proper formation and function of neurons has been proposed.